Chimeric particles

Abstract

The present invention relates to chimeric infectious particles, as well as panels, compositions pharmaceutical formulations and kits thereof, as well as methods of producing the same and uses thereof, in particular uses in therapy and diagnosis.

Description

[0001] CHIMERIC PARTICLES

[0002] SEQUENCE LISTING

[0003] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled P80591WO_Seq List_For filing.xml, created on 04 February 2026, which is 45.3 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2’-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2’-OH in place of one 2’-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of an uracil of RNA). Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and / or DNA, unless otherwise stated, including, but not limited to such nucleic acids having modified nucleobases.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to chimeric infectious particles, as well as panels, compositions pharmaceutical formulations and kits thereof, as well as methods of producing the same and uses thereof, in particular uses in therapy and diagnosis.

[0006] BACKGROUND

[0007] Drug-resistant pathogens are becoming a serious issue in both human pathology and the livestock industry. Infectious diseases rank as the second leading cause of death in humans, accounting for 25% of global mortality, with bacterial infections being a significant contributor. Antibiotic resistance in bacteria has now emerged as a major international public health crisis. In North America alone, drug-resistant bacteria are responsible for over 60% of hospital-acquired infections.

[0008] In the livestock industry, farmers face substantial economic losses due to antibioticresistant bacterial infections, with the prevalence of resistant organisms steadily increasing on most farms. It is estimated that 60-80% of cattle, sheep, swine, and poultry in the U. S. are regularly given antibiotics, primarily to promote growth. This widespread overuse of antibioticsin livestock significantly contributes to the development of antibiotic resistance in both animals and humans.

[0009] Bacteriophages, or phages, offer a promising alternative to combat antibiotic resistance. These viruses are naturally abundant and exist wherever their bacterial hosts are found. They specifically target and infect their host bacteria without affecting unrelated bacteria or mammalian cells, making them a highly attractive solution to the growing problem of antibiotic resistance.

[0010] Other phage-like infectious particles have been described in the art. The present inventors previously described a new family of mobile genetic elements (MGEs), the phageinducible chromosomal islands (PICIs) (Penades et al. (2015). Annual Review of Virology 2, 181-201). These are small (~10-15 kb), chromosomally integrated elements that are extremely widespread in nature, being present in more than 200 species, with many strains containing two or more of these elements (de Sousa et al. (2023). Nucleic Acids Res 51, 2759–2777). PICIs are intimately related to certain temperate (helper) phages, whose life cycles they parasitise. In the presence of active helper phages, and once induced, PICIs replicate extensively, then excise from the bacterial chromosome and are efficiently packaged into infectious particles composed of helper phage virion proteins, which mediate the high intra species transfer of these genetic elements.

[0011] The inventors have also described specific phage satellites: capsid-forming PICIs (cf-PICIs). Unlike other PICIs and other phage satellites, including P4, PLE, or PICMIs, whose packaging and production of infective satellite particles depend entirely on the helper phage, cf-PICIs have the unique ability to produce small PICI-sized capsids and package PICI DNA exclusively into these capsids. (Alqurainy et al (2023). Cell Host Microbe 31, 69-82. e5.). The cf-PICI-encoded genes that produce specific PICI capsids show sequence similarity to phage genes. Intriguingly, to make the cf-PICI capsids, the proteins encoded by cf-PICI genes interact exclusively with other cf-PICI encoded proteins, not phage counterparts.

[0012] Bacteria and bacteriophage and phage satellites, as well as other phage-related elements are in a constant arms race. Bacteria develop resistance to phage through a range of mechanisms such as spontaneous mutations, restriction modification systems, adaptive immunity via the CRISPR-Cas system and horizontal gene transfer (HGT) between bacterial species. Although phage resistance in bacteria develops approximately 10-fold more slowly than antibiotic resistance, it is still a roadblock to widespread clinical and industrial use of phage. Further, the specificity of phage tropism for their host cells means that conventional applications of phage technology often require individual phage products to be produced for a single bacterium ora limited range of bacteria (e.g. a handful of strains within a single species). It would be desirable to overcome this specificity issue, and to have a tool kit which allows for the production of phage with host cell tropisms to bacteria of clinical or industrial interest.It is therefore the object of this invention to overcome one or more of the above problems. In particular, the present invention seeks to provide phage-related particles wherein the tropism can be determined by the user, targeting specific strains of a single species or all members of that species or even multiple species, providing a platform by which phage-based technologies can be applied to a wide range of applications, including clinical applications.

[0013] SUMMARY

[0014] The present inventors have shown for the first time that a recently identified class of phage satellites, cf-PICIs are capable of producing capsids and loading these capsids with PICI DNA, and that these cf-PICI capsids can parasitise tails from a range of phages, phage satellites and phage-related elements to produce chimeric particles which are capable of infecting host bacteria. The promiscuous nature of the cf-PICI capsids and their ability to form chimeric infectious particles with a range of tails is entirely unprecedented. To facilitate this ability, cf-PICI are able to produce tail-less capsids loaded with DNA, and these elements are stable and capable of release into the environment. Furthermore, the present inventors have elucidated for the first time herein a surprising mechanism wherein isolated tails are able to bind to a bacterium, facilitating the recruitment of DNA-loaded tail-less capsid elements, which can then transfer their DNA into the bacterium.

[0015] Accordingly, the present invention provides a chimeric infectious particle comprising: (a) a capsid from a first phage, phage satellite or phage-related element; and (b) a tail from a second phage, phage satellite or phage-related element; wherein the first and second phage, phage satellite or phage-related elements are different.

[0016] The present invention provides a chimeric infectious particle comprising: (a) a capsid from a first phage, phage satellite or phage-related element; and (b) a tail from a second phage, phage satellite or phage-related element; wherein the first and second phage, phage satellite or phage-related elements are not endogenous to the same bacterial species and / or strain.

[0017] The present invention provides a chimeric infectious particle comprising: (a) a capsid from a first phage, phage satellite or phage-related element; and (b) a tail from a second phage, phage satellite or phage-related element; wherein the first and second phage, phage satellite or phage-related elements are different and the first and second phage, phage satellite or phage-related elements are not endogenous to the same bacterial species and / or strain.

[0018] The first phage, phage satellite or phage-related element may be selected from the group consisting of: (a) a phage satellite, optionally a capsid-forming PICI (cf-PICI), a phage inducible chromosomal islands (PICI), a P4-like satellite, ora PICI-like element (PLE); and (b) a phage from the order Caudovirales, optionally a phage from the family Podoviridae,Siphoviridae or Myoviridae. The first phage, phage satellite or phage-related element may be: (a) a capsid-forming PICI (cf-PICI), optionally selected from the group consisting of KpCIDSM30104, EcCIGN02175, EcCIEDL, EcCISMS-3-5, EcCIPNUSAE044409, SeCIDerby, YaCI159, SfCI301, SfCI8401, EcCIIAI39, CfCICFNIH4, EcCIEC11-7286, EcCIEDIa, EcCIWW223, EpCIETW41, PgCIFDAARGOS.186, SdCICCFSAN010956, SeCIFDA336426-1, PmCIATCC29906, EcCIEO709, EcCIRM10386, KvCIGJ3, ECCICFSAN002236, EcCID8, EcCIRM10042, CpCITV06, EcCIHUST159, SeCI08-1209, EcCI392917, SeCIKentucky, GaCISCGC, GaCIWKBI, KpCIAR.0148, EcCIEDL933, ECCI144, ECCIPA40, SeCI7830, EcCIST130, KpCIKPNOI, EcCIPSUO103, KoCICAV175, XnCIATCC1906, EcCI315650, B..kocchi. BDGP4, B.cereus. BAG6X1-2, S.saprophyticus. CCUG38042, C.botulinum. B. Eklund.17B, S.pettenkoferi.589, S.haemolitycus. S167, S. equorum. DSM15097, S.aureus. VET0180R, S.xylosus. HKUOPL8, C.beijerinckii. WB53, S.arlettae.lOV5, S.. aureus. C0673, E.durans.4928STDY7071318, S.warneri. DE0454, L.rhammosus. GG, B.thuringiensis. BGSC.4W1.4W1, L.casei. Lc705, C.sporogenes.87-0535, S.hominis. SNUC.5746, L.casei. BL23; (b) a PICI, optionally selected from the group consisting of EcCI11368.1, EcCIIHE3034, EcCIRM13514, EcCIRM12579, EcCIATCC_25922, EcCI042, PcCIPCC221, EcCIDi14, SbCISb277, PmCIOH1905, PhaCIATCC43949, EcCICFT073, EcCI11128, SAPI1, LICIKF147, LICIA76-1, SaPlmw2, SAPI2, SpnCITaiwan-0.2, SpnCITaiwan-0.03, SpnCI-A45-1.9, SaPIbovI, LICISK11, SpnCITCH8341-0.25, SpnCIINV104-1.06, EfCIV583, MG1363-1 and LICI-CV56-1; (c) a PICI-like element (PLE), optionally selected from the group consisting of PLE1, PLE2, PLE3, PLE4 and PLE5; (d) a P4-like satellite, optionally selected from the group consisting of P4-like satellites from any of Lelliottia amnigena, Escherichia coli, Shigella boydii, Klebsiella pneumoniae, Salmonella enterica, Klebsiella variicola, Klebsiella sp., Shimwellia blattae, Escherichia albertii, Enterobacter cloacae, Enterobacter hormaechei, Citrobacter freundii, Cronobacter malonaticus, Escherichia fergusonii, Buttiauxella sp., Enterobacteriaceae bacterium, Citrobacter werkmanii, Kluyvera intermedia, Escherichia marmotae, Enterobacter sp., Cedecea lapagei, Klebsiella oxytoca, Raoultella ornithinolytica, Cronobacter muytjensii, Salmonella sp., Kosakonia cowanii, Enterobacter roggenkampii, Kosakonia sp., Metakosakonia sp., Citrobacter sp., Klebsiella quasipneumoniae, Citrobacter portucalensis, Klebsiella michiganensis, Klebsiella aerogenes, Kosakonia sacchari, Cronobacter sakazakii, Enterobacter kobei, Raoultella planticola, Atlantibacter hermannii, Pantoea vagans, Pantoea alhagi, Mixta calida, Erwinia billingiae, Pantoea sp., Erwinia sp., Pantoea rwandensis, Pantoea ananatis, Tatumella ptyseos, Edwardsiella sp., Edwardsiella piscicida, Edwardsiella tarda, Edwardsiella anguillarum, Hafnia sp., Hafnia alvei, Pectobacterium wasabiae, Pectobacterium carotovorum, Pectobacterium atrosepticum, Pectobacterium polaris, Pectobacteriumparmentieri, Serratia sp., Serratia marcescens, Yersinia enterocolitica, Yersinia aldovae, Yersinia ruckeri, Serratia fonticola, Serratia plymuthica, Yersinia sp., Yersinia massiliensis, Serratia liquefaciens, Yersinia frederiksenii, Serratia nematodiphila or Yersinia similis; (e) a Siphoviridae phage, optionally selected from the group consisting of E. coii phages lambda, 80, HK97, HK106, HK022, T1, and T5; Staphylococcus aureus phages φ11 and 80α, Salmonella enterica BTP1; and Lactococcus lactis TP901-1; (e) a Myoviridae phage, optionally selected from the group consisting of E. coli phages T4, P1, P2, Mu, T2; Bacillus subtilis SPO1; Staphylococcus aureus phages φK, φ812, φMR11; (g) a Podoviridae phage, optionally selected from the group consisting of E. coli phage T7; Salmonella enterica P22; Bacillus subtilis phi29; Streptococcus pneumoniae CP-1; Staphylococcus aureus φ44RR2.8t; or (h) a phage selected from the group consisting of E. coli phages M13, MS2, PhiX174, Pseudomonas syringae phage φ6, Vibrio cholerae phage Autolykivirus, Acinetobacter baumannii phage φAb1, PRD1 phage, and cyanophage. The first phage, phage satellite or phage-related element may be a capsid-forming PICI (cf-PICI) selected from the group consisting of KpCIDSM30104, EcCIGN02175.

[0019] The capsid may comprise or consist of a plurality of mature capsid proteins each comprising or consisting of an amino acid sequence comprising or consisting of at least 60% sequence identity to any one of SEQ ID NOs: 1 to 7, optionally any one of SEQ ID NOs: 1 to 3; preferably each mature capsid proteins comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 1 to 7, optionally anyone of SEQ ID NOs: 1 to 3.

[0020] The second phage, phage satellite or phage-related element may be a phage. The phage may be selected from the group consisting of: (a) a Siphoviridae phage, optionally selected from the group consisting of E coll phages lambda, 80, HK97, HK106, HK022, T1, and T5; Staphylococcus aureus phages φ11 and 80α, Salmonella enterica BTP1; and Lactococcus lactis TP901-1; (b) a Myoviridae phage, optionally selected from the group consisting of E. coli phages T4, P1, P2, Mu, T2; Bacillus subtilis SPO1; Staphylococcus aureus phages φK, φ812, φMR11; (c) a Podoviridae phage, optionally selected from the group consisting of E. coli phage T7; Salmonella enterica P22; Bacillus subtilis phi29; Streptococcus pneumoniae CP-1; Staphylococcus aureus φ44RR2.8t; or (d) a phage selected from the group consisting of E. coli phages M13, MS2, PhiX174, Pseudomonas syringae phage φ6, Vibrio cholerae phage Autolykivirus, Acinetobacter baumannii phage φAb1, PRD1 phage, and cyanophage. Optionally the chimeric particle comprises a tail comprising or consisting of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity to any one of SEQ ID NOs: 20 to 26, particularly a major tail protein which has an amino acid sequence of any one of SEQ ID NOs: 20 to 26.In a chimeric particle of the invention: (a) the capsid may further comprise a neck which is configured to connect the capsid from the first phage, phage satellite or phage-related element with the tail from the second phage, phage satellite or phage-related element; and / or (b) the tail may comprise an amino acid sequence which is configured to connect to the capsid from the first phage, phage satellite or phage-related element, preferably which is configured to connect to the neck of the capsid from the first phage, phage satellite or phage-related element. The neck may comprise or consist of: (a) a capsid-tail adaptor polypeptide which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity to any one of SEQ ID NOs: 8 to 12, particularly any one of SEQ ID NOs: 8 to 10; (b) a capsid-tail connector polypeptide which comprises or consists of an amino acid sequence comprising or consisting of has at least 60% sequence identity to any one of SEQ ID NOs: 13 to 17, particularly any one of SEQ ID NOs: 13 to 15; and / or (c) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of has at least 60% sequence identity to any one of SEQ ID NOs: 35 to 37. The neck may comprise or consist of: (i) a capsid-tail adaptor polypeptide which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 8 to 12, particularly any one of SEQ ID NOs: 8 to 10; and / or (ii) a capsid-tail connector polypeptide which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 13 to 17, particularly any one of SEQ ID NOs: 13 to 15; and / or (iii) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 35 to 37.

[0021] The capsid may be capable of interacting with: (a) a tail from a single second phage, phage satellite or phage-related element; or (b) a tail from two or more different second infectious phage, phage satellites or phage-related elements.

[0022] A chimeric particle of the invention may be capable of infecting: (a) a single bacterial species or strain thereof; (b) two or more different bacterial species; and / or (c) two or more strains of a single bacterial species.

[0023] A chimeric particle of the invention may further comprise a nucleic acid molecule, optionally wherein: (a) said nucleic acid molecule is DNA or RNA; and / or (b) the nucleic acid molecule is an exogenous nucleic acid molecule compared with the nucleic acid molecule of the first phage, phage satellite or phage-related element and / or the nucleic acid molecule of the second phage, phage satellite or phage-related element, preferably wherein the nucleic acid molecule is an exogenous nucleic acid molecule compared with the nucleic acid molecules of both the first and second phage, phage satellite or phage-related element. The nucleic acid molecule may encode: (a) encode a protein capable of killing one or more target bacteria, optionally: (i)an antibiotic and / or a protein which reduces antibiotic resistance; or (ii) a lytic enzyme; (b) encode a reporter protein, e.g. a fluorescent protein or an enzymaticmarker; (c) encode a protein which alters the physiology of the target bacteria; and / or (d) modify the genome of one or more target bacteria.

[0024] A chimeric particle of the invention may comprise a capsid from a first phage, phage satellite or phage related element which is a phage and a tail from a second phage, phage satellite or phage related element which is a phage.

[0025] The invention also provides a panel comprising two or more chimeric particles of the invention may, wherein the two or more chimeric particles target the same or different bacterial species and / or strains, optionally wherein each of the two or more chimeric particles target at least one different bacterial species and / or strain. The two or more chimeric particles in a panel may comprise: (a) the same capsid and different tails; (b) different capsids and the same tails; or (c) different capsids and different tails.

[0026] The invention also provides a composition comprising or consisting of: (a) a capsid from a first phage, phage satellite or phage-related element; and (b) a tail from a second phage, phage satellite or phage-related element; wherein the first and second phage, phage satellite or phage-related element are different and / or the first and second phage, phage satellite or phage-related elements are not endogenous to the same bacterial species and / or strain, wherein the capsid and the tail are capable of assembling to form a chimeric infectious particle of the invention. A composition of the invention may comprise: (a) two or more different capsids; and / or (b) two or more different tails.

[0027] The invention further provides a pharmaceutical formulation comprising chimeric particle of the invention, a panel of the invention, or a composition of the invention, and at least one pharmaceutically acceptable carrier.

[0028] The invention also provides a kit of parts comprising or consisting of: (a) first composition comprising or consisting of a capsid from a first phage, phage satellite or phage-related element; and (b) a second composition comprising or consisting of a tail from a second phage, phage satellite or phage-related element; wherein: the first and second pharmaceutical compositions are stored in separate containers; and the first and second phage, phage satellite or phage-related element are different and / or the first and second phage, phage satellite or phage-related elements are not endogenous to the same bacterial species and / or strain, wherein the capsid and the tail are capable of assembling to form a chimeric infectious particle of the invention. Optionally said kit comprises two or more first compositions each comprising a different capsid and / or two or more second compositions each comprising a different tail. Further optionally wherein the kit of parts may further comprise instructions for use.

[0029] The invention further provides a tail-less capsid from a phage, phage satellite or phage related element, which comprises a nucleic acid molecule. In a tail-less capsid of the invention: (a) the phage, phage satellite or phage-related element may be as herein; (b) the capsid mayfurther comprise a neck which is configured to connect the capsid from the first phage, phage satellite or phage-related element with the tail from the second phage, phage satellite or phage-related element, wherein optionally said neck is as defined herein; and / or (c) the capsid may be capable of interacting with (i) a tail from a single second phage, phage satellite or phage-related element or (ii) a tail from two or more different second infectious phage, phage satellites or phage-related elements; (d) the nucleic acid molecule is as defined herein; (e) the tail-less capsid is non-enveloped and / or (f) the tail-less capsid may be in isolated form.

[0030] The invention also provides a panel of tail-less capsids of the invention, which comprises two or more different tail-less capsids.

[0031] The invention further provides an isolated tail from a phage, phage satellite or phage-related element, wherein the tail is capable of assembling with a tail-less capsid of the invention to form a chimeric infectious particle of the invention. An isolated tail of the invention: (a) the phage, phage satellite or phage-related element may be as herein; (b) the isolated tail from a second phage, phage satellite or phage-related element may be capable of assembling with the tail-less capsid of a first phage, phage satellite or phage-related element capsid via a neck comprised in the tail-less capsid, wherein optionally said neck may be as herein; and / or (c) the isolated tail may be capable of interacting with (i) a tail-less capsid from a single first phage, phage satellite or phage-related element or (ii) a tail-less capsid from two or more different first phage, phage satellites or phage-related elements.

[0032] The invention also provides a panel of isolated tails of the invention, which comprises two or more different tails.

[0033] The invention also provides a kit of parts comprising or consisting of: (a) a first composition comprising or consisting of a tail-less capsid from a first phage, phage satellite or phage-related element as defined herein ora panel of tail-less capsids as defined herein; and (b) a second composition comprising or consisting of an isolated tail from a second phage, phage satellite or phage-related element as defined herein, or a panel of isolated tails as defined herein. Optionally the first and second compositions are stored in separate containers; and the first and second phage, phage satellite or phage-related element are different, wherein the tail-less capsid and the isolated tail are capable of assembling to form a chimeric infectious particle of the invention. Optionally said kit may further comprise instructions for use.

[0034] The invention also provides a nucleic acid comprising or consisting of: (a) a nucleotide sequence encoding a capsid from a first phage, phage satellite or phage-related element; and / or (b) a nucleotide sequence encoding a tail from a second phage, phage satellite or phage-related element; wherein the first and second phage, phage satellite or phage-related element are different and / or the first and second phage, phage satellite or phage-related elements are not endogenous to the same bacterial species and / or strain, wherein the capsid and the tail are capable of assembling to form a chimeric infectious particle of the invention.Optionally: the nucleotide sequence encoding the capsid and / or the nucleotide sequence encoding the tail are operably linked to a promoter; or the nucleotide sequence encoding the capsid and / or the nucleotide sequence encoding the tail are in a polycistronic cassette. Further optionally said nucleic acid further comprises a nucleic acid sequence which will be contained within the capsid of the chimeric particle.

[0035] The invention further provides an expression vector comprising a nucleic acid of the invention.

[0036] The invention also provides a bacterial cell comprising a nucleic acid of the invention or an expression vector of the invention. Optionally said bacterial cell comprises: (a) a single nucleic acid or expression vector encoding the capsid; (b) a single nucleic acid or expression vector encoding the tail; (c) a single nucleic acid or expression vector encoding the capsid and the tail; or (d) a first nucleic acid or expression vector encoding the capsid and a second nucleic acid or expression vector encoding the tail. Further optionally, said nucleic acid or expression vector further comprises a nucleic acid sequence which will be contained within the capsid of the chimeric particle.

[0037] The invention also provides a method of producing a chimeric infectious particle of the invention, said method comprising: (a) culturing a bacterial cell of the invention under conditions for production of a chimeric infectious particle, wherein optionally said method further comprises purifying the resulting chimeric particle; or (b) (i) culturing a first bacterial cell of the invention to produce the capsid under conditions for production of the capsid; (ii) culturing a second bacterial cell of the invention to produce the tail under conditions for production of the tail; and (iii) combining the capsid produced in step (i) with the tail produced in step (i) to form a chimeric particle; wherein optionally said method further comprises purifying the capsid, tail and / or chimeric particle.

[0038] The invention further provides a method of producing a chimeric infectious particle, said method comprising contacting an isolated capsid from a first phage, phage satellite or phage-related element with an isolated tail from a second phage, phage satellite or phage-related element in conditions that allow for the assembly of the capsid and the tail to result in a chimeric infectious particle, wherein: the first and second phage, phage satellite or phage-related elements are different and / or the first and second phage, phage satellite or phage-related elements are not endogenous to the same bacterial species and / or strain. Optionally: (i) said method further comprises purifying and / or isolating the resulting chimeric infectious particle; (ii) said capsid is a tail-less capsid as herein; and / or (iii) said chimeric infectious particle is as defined herein.

[0039] The invention also provides a chimeric infectious particle, obtainable by the method of the invention, wherein optionally said chimeric infectious particle is as defined herein.The invention further provides a pharmaceutical formulation comprising a bacterial cell of the invention and at least one pharmaceutically acceptable carrier.

[0040] The invention further provides a chimeric infectious particle, panel, nucleic acid, expression vector, bacterial cell, composition or pharmaceutical formulation of the invention for use in a method of therapy. The therapy may be for treating a subject, preferably a mammalian subject, more preferably a human subject. The therapy may be for: (a) treating and / or preventing a bacterial infection; and / or (b) modulating the gut microbiome to improve digestion and / or immunity. The bacterial infection may be selected from respiratory infections, urinary tract infections, skin and soft tissue infections, bloodstream infections (sepsis), gastrointestinal infections, bone and joint infections (osteomyelitis, septic arthritis), meningitis, endocarditis, wound infections, peritonitis, otitis media, sinusitis, dental infections (abscesses), pelvic inflammatory disease, eye infections (conjunctivitis, keratitis), infections that are generated by Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis, Pseudomonas aeruginosa, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, Clostridium difficile, Shigella spp., Vibrio cholerae, Kingella kingae, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus viridans, Enterococcus faecalis, Bacteroides fragilis, Moraxella catarrhalis, Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Chlamydia trachomatis or other relevant pathogens and / or multiple drug resistant bacterial infection.

[0041] The invention also provides the use of a chimeric infectious particle, panel, nucleic acid, expression vector, bacterial cell, composition or pharmaceutical formulation of the invention for: (a) drug discovery, such as discovery of antimicrobial agents; (b) antibacterial treatment of agricultural products such as foodstuffs and animal feed; (c) decontamination of contaminated environments, optionally clinical environments, food-processing environments or water distribution systems; (d) degradation and / or prevention of biofilms; (e) controlling plant disease; (f) improving plant yield; (g) disinfecting water sources; (h) research; (i) biodefence; and / or (j) nanotechnology, such as nanomaterial templates or developing drug delivery systems.

[0042] The invention also provides a method of diagnosing infection with a bacterial species and / or bacterial strain of interest, said method comprising: (a) contacting a sample obtained from a subject with a chimeric infectious particle, panel, nucleic acid, expression vector, bacterial cell, composition or pharmaceutical formulation of the invention, wherein the chimeric particle comprises a nucleic acid molecule comprising a reporter gene or encoding a reporter protein; and (b) detecting the reporter gene or protein; wherein a positive signal for the reporter gene or protein indicates the presence of an infection by a bacterial species and / or strain which is susceptible to infection by the chimeric particle. Optionally wherein two or moredifferent chimeric particles capable of infecting different bacterial species and / or strains are used, said two or more different chimeric particles each comprising a nucleic acid molecule comprising a different reporter gene or encoding a different reporter protein, such that the different bacterial species and / or strains can be differentiated based on the reporter gene or protein detected.

[0043] The invention also provides a method of treatment comprising the step of: (a) identifying the pathologic bacterial species and / or strains present in a subject; and (b) providing to the subject a therapeutically effective amount of a chimeric infectious particle, panel, nucleic acid, expression vector, bacterial cell, composition or pharmaceutical formulation of the invention which target the identified pathologic bacterial species and / or strains present in the subject; wherein optionally said method of treatment comprises identifying the pathologic bacterial species and / or strains present in the subject by a method of the invention.

[0044] The invention further provides a tail-less capsid or a panel of tail-less capsids of the invention and an isolated tail or panel of isolated tails of the invention for use in a method of therapy. The therapy may be for treating a subject, preferably a mammalian subject, more preferably a human subject. The method of therapy may comprise the steps of: (a) administering a therapeutically effective amount of an isolated tail, or a panel of isolated tails of the invention to the subject in need thereof; and (b) subsequently administering a therapeutically effective amount of a tail-less capsid, or a panel of tail-less capsids of the invention to the subject in need thereof. Step (b) may be performed no more than about 24h after step (a), no more than about 12h after step (a), no more than about 8h after step (a), no more than about 4h after step (a), no more than about 2h after step (a) or no more than about 1h after step (a). The therapy may be for: (a) treating and / or preventing a bacterial infection; and / or (b) modulating the gut microbiome to improve digestion and / or immunity. The bacterial infection may be selected from respiratory infections, urinary tract infections, skin and soft tissue infections, bloodstream infections (sepsis), gastrointestinal infections, bone and joint infections (osteomyelitis, septic arthritis), meningitis, endocarditis, wound infections, peritonitis, otitis media, sinusitis, dental infections (abscesses), pelvic inflammatory disease, eye infections (conjunctivitis, keratitis), infections that are generated by Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis, Pseudomonas aeruginosa, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, Clostridium difficile, Shigella spp., Vibrio cholerae, Kingella kingae, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus viridans, Enterococcus faecalis, Bacteroides fragilis, Moraxella catarrhalis, Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Chlamydia trachomatis or other relevant pathogens and / or multiple drug resistant bacterial infection.The invention also provides a method of diagnosing infection with a bacterial species and / or bacterial strain of interest, said method comprising: (a) contacting a sample obtained from a subject with an isolated tail or panel of isolated tails of the invention; (b) contacting the sample obtained from the subject with a tail-less capsid, or a panel of tail-less capsids of the invention; wherein the tail-less capsid or panel of tail-less capsids comprises a nucleic acid molecule comprising a reporter gene or encoding a reporter protein; and (c) detecting the reporter gene or protein wherein a positive signal for the reporter gene or protein indicates the presence of an infection by a bacterial species and / or strain which is susceptible to recognition by the isolated tail or panel of isolated tails. The sample may be washed at least one, at least twice or at least three times, between steps (a) and (b).

[0045] The invention also provides a method of treatment comprising the step of: (a) identifying the pathologic bacterial species and / or strains present in a subject; and (b) providing to the subject a therapeutically effective amount of an isolated tail or panel of isolated tails of the invention which target the identified pathologic bacterial species and / or strains present in the subject; and (c) subsequently providing to the subject a therapeutically effective amount of a tail-less capsid or a panel of tail-less capsids of the invention; wherein optionally said method of treatment comprises identifying the pathologic bacterial species and / or strains present in the subject by a method of the invention.

[0046] BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 - Induced cf-PICIs have low intra-species transfer. (A) A comparative map between cf-PICIs EcCIGN02175 and KpCIDSM30104. Genes are coloured based on their function. Grey scales between cf-PICIs indicate the regions that share similarity, identified by BLASTn. (B, C) Transfer of EcCIGN02175 (B) or KpCIDSM30104 (C) to different bacterial species. E. coli GN02175 or K. pneumoniae DSM30104 strains were MC-induced, and the resulting lysates were tested for transduction. The recipient strains were E. coli JP24699, K. pneumoniae JP24460, Citrobacter freundii 2H5, Citrobacter koseri 2F8, Salmonella enterica JP18938, Enterobacter cloacae ATCC13047, and Enterobacter hormaechei Ehh_18. Values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. Error bars represent the standard deviation, n = 4 independent samples. DL: Detection limits.

[0048] (D, E) Induction of EcCIGN02175 or KpCIDSM30104 by resident prophages. E. coli GN02175 or K. pneumoniae DSM30104 strains were MC induced, and samples were taken at the indicated time points (hours) for DNA analyses. DNAwas separated on a 0.7% agarose gel, followed by Southern blotting analysis using specific EcCIGN02175 (D) or KpCIDSM30104 (E) probes. L: Southern blot molecular marker (DNA molecular weight marker). CCC: Covalently closed circular.Figure 2 - cf-PICIs naturally produce tail-less particles. (A) Packaged DNA extracted from lysates after induction of different DSM30104 derivatives was separated on a 0.7% agarose gel. KpCI: KpCIDSM30104. ‘+’ indicates the presence of P1, P2, or KpCIDSM30104 in the donor strain. (B) Southern blot analyses of the samples obtained in panel A, using KpCIDSM30104 or P1-specific probes. (C) Electron microscopy images of tail-less cf-PICIs. Left: Image showing capsids present in the lysate of the induced WT DSM30104 strain. Right: Image showing the KpCIDSM30104 capsids obtained after induction of the DSM30104 derivative mutant in P2 and in the capsid gene of P1. Capsid particles are highlighted with a frame.

[0049] Figure 3 - Formation of chimeric cf-PICIs promotes inter-generic transfer. (A) Intra- or inter-species transfer of KpCIDSM30104 by the formation of chimeric infective particles. The lysate obtained after induction of the K. pneumoniae DSM30104 Aphage P2 strain (JP24853) was mixed with the lysate obtained after induction of HK022 or HK106 prophage mutants in their respective capsid genes, and then the transfer of the KpCIDSM30104 island to K. pneumoniae JP24460 (left) or E. coli C1a (right) was evaluated. Values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. Error bars indicate the standard deviation. A t-test was used to compare the means of control and samples with additional phage tails after log-io transformation, ns: P > 0.05. *“*: P < 0.0001. n = 4 independent samples.

[0050]

[0051] represents the control where cf-PICIs were mixed with LB. DL: Detection limits. (B) The chimeric particles have a host range that depends on the hijacked tails. The lysate containing the tail-less KpCIDSM30104 particles was mixed with HK022 tails, and the transfer of KpCIDSM30104 to different species was evaluated. Recipients were E. coli (C1a, RHBSTW-00139, EDL933, and JP24699), Citrobacter freundii 2H5, Citrobacter koseri 2F8, Salmonella enterica JP18938, Enterobacter cloacae ATCC13047, and Enterobacter hormaechei Ehh_18. Values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. Error bars indicate the standard deviation, n = 4 independent samples. DL: Detection limits. (C) Negative stain electron microscopy image of KpCIDSM30104 after incubation with HK022 phage tails, yielding assembled virion particles (frames). Excess free HK022 tails are also shown (arrows). (D) Induction of WT phage HK022 produces tails in excess for the inter-generic transfer of KpCIDSM30104. The lysates obtained after induction of the K. pneumoniae JP24853 strain were mixed with the lysates obtained after induction of the WT E. coli HK022 lysogen, or with lysates obtained after induction of the HK022 capsid and major tail mutant prophages, and the transfer of KpCIDSM30104 to E. coli strain C1a was evaluated. Values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. Error bars indicate the standard deviation. After log-iotransformation, a One-way ANOVA was conducted, followed by a Dunnett’s multiple comparisons test to compare the sample with exogenous WT HK022 lysate to other samples, n = 4 independent samples, ns: P > 0.05. *“*: P < 0.0001. KpCI: KpCIDSM30104. WT: wildtype.

[0052] Figure 4 - Tail-less cf-PICIs are frequently released into natural environments and transmit within microbiota. Intra-species transfer of EcCIGN02175 (A) or EcCIEDL933 (B) to C1 a. Natural E. coli GN02175 and EDL933 strains, carrying EcCIGN02175 or EcCIEDL933 respectively, were MC-induced, and the resulting lysates were tested for transduction in the presence or absence of lysates obtained after induction of WT HK106 or HK022 lysogens. Values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. Error bars indicate the standard deviation.

[0053]

[0054] represents the control where cf-PICIs were mixed with LB. A t-test was used to compare the data between samples with no exogenous phage (control) and other samples after log10transformation. *: P ≤ 0.05. ****: P ≤ 0.0001. n = 4 independent samples. (C) cf-PICIs are produced in the absence of an inducing helper prophage. The non-lysogenic K. pneumoniae JP24871 strain, carrying KpCIDSM30104, was grown until OD600 = 0.2. Then, the strain was cultured in the presence of lytic phage K68 QB (MOI= 0.01), lysozyme (500 μg / mL), or ampicillin (50 pg / mL). As a control, non-treated cells were also grown. The resulting filtered lysates were mixed with HK022 lysates and tested for transduction to E. coli C1a. Values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. Error bars indicate the standard deviation. A t-test was used to compare the data between samples with no treatment and the other samples after log transformation. ****: P < 0.0001. n = 4 independent samples.

[0055] (D) Inter-species transfer occurs naturally in mixed populations. K. pneumoniae JP24853, carrying both P1 and KpCIDSM30104, was co-cultured with either the E. coli HK022 or HK106 lysogens in the presence of the E. coli strain JP24888, used here as the recipient for KpCIDSM30104. Strains were mixed at a ratio of 1:1:1 for 5 hours and then plated in the presence of both kanamycin (for KpCIDSM30104) and tetracycline (for JP24888). Values are presented as means of colony-forming units (CFU) per milliliter of co-culture. Error bars indicate the standard deviation, n = 4 independent samples. DL: Detection limits. (E) Presence of cf-PICI EcCIGN02175 in human metagenome studies. Genes are coloured according to their sequence and function. Grey scales between cf-PICI sequences indicate regions of similarity identified by BLASTn. The overall identity between both islands is 99.95%.

[0056] Figure 5 - The cf-PICI-encoded tail adaptor and connector proteins determine tail specificity. (A) Inter-species transfer of EcCIGN02175 from E. coli GN02175 to E. hormaechei Ehh_18 JP25170 (Ehh_18 AEhCIEhh_18). The E. coli strain GN02175 wasinduced, and the lysate mixed with that obtained after MC induction of E. hormaechei Ehh_18 JP25170. The transfer of EcCIGN02175 is quantified. No transfer was observed in the absence of the E. hormaechei Ehh_18 JP25170 lysate. (B) Intra-species transfer of EcCIGN02175. The E. hormaechei Ehh_18 JP25149 strain carrying GN02175 was induced, and the transfer of the island to E. hormaechei Ehh_18 JP25170 (Ehh_18 AEhCIEhh_18) was analysed. (C) Inter-species transfer of EcCIGN02175 from the E. hormaechei Ehh_18 derivative JP25149 to E. coll C1a was analysed in the presence of the lysate obtained after induction of the HK106 prophage. (D) Intra-species transfer of KpCIDSM30104 in E. coli. The lysate obtained after induction of the E. coli GN02175 derivative JP25235 carrying KpCIDSM30104 was mixed with the lysate obtained after induction of the HK022 prophage, and the transfer of the island was analysed. represents the cf-PICI sample with no phage lysate added. In (A), (B), (C), and (D), values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. Error bars indicate standard deviation, n = 4 independent samples. In (C) and (D), a t-test was used after a log-io transformation. ****: P < 0.0001. (E) cf-PICIs evolve their adaptor and connector proteins to interact with different phage tails. The strain carrying KpCIDSM30104 mutated in its adaptor and connector genes was complemented with different adaptor and connector genes from other cf-PICIs. These strains were MC- and L-arabinose-induced. The resulting lysates were tested for KpCIDSM30104 transfer in the presence of the lysates obtained after induction of the HK022 or HK106 prophages. E. coli C1a was used as the recipient strain in these experiments. Values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. Error bars indicate standard deviation. A two-way ANOVA with Sidak’s multiple comparisons test was performed after a log-io transformation. ****: P < 0.0001. n = 4 independent samples, ada & con: adaptor and connector gene. EcCI: EcCIGN02175. KpCI: KpCIDSM30104. EDL: EcCIEDL933. DL: Detection limits.

[0057] Figure 6 - Structure of the EcCIEDL933 capsid. (A) Organisation of the EcCIEDL933 genome, highlighting the maturation of the protein product of gene 1786, yielding the 93-327 stretch of the mature capsid protein (MCP). (B) Negative stain electron microscopy image of the infective particle of EcCIEDL933, comprised of the island-encoded capsid and the hijacked tail of the co-residing HK106 tail. (C) 3.24 A resolution map of the EcCIEDL933 capsid with diameter of 47.5 nm and T=4 icosahedral symmetry made up of pentameric and hexameric capsomers (pentons and hexons, shown in orange and green, respectively). (D) Side chain features of the atomic model (green) and the corresponding map density section (grey) of a representative a-helix (top) and p-sheet (bottom). (E) Atomic model of the asymmetric unit and the corresponding density maps of the hexon (green) and penton (orange), showing their respective dimensions and the angle between them. (F) Structure of the EcCIEDL933 MCPoverlaid on the HK97 MCP (PDB ID: 1OHG), showing a nearly perfect match between the structure, with the main divergence coming from the 227-248 connector loop. (G) Root mean square deviation (RMSD) between the EcCIEDL933 and HK97 MCP.

[0058] Figure 7 - Interaction details between EcCIEDL933 capsomers and within them. To represent intercapsomere interactions, a penton (P) and three hexons (H1-H3) were used in the analysis. (A, B) Penton-hexon interactions are established by two anti-parallel N-arms around a twofold axis (A) and between a pentamer and two hexamers around a threefold axis (B). (C, D) Similarly, hexon-hexon interactions are formed around the twofold axis (C) and threefold axis (D). (E) The detailed interaction network of the asymmetric unit of the threefold axis interaction shown in (E), salt bridges are marked with yellow dashed lines. (F) Electrostatic surface potential of the interaction shown in (D) without the E-loops (shown in orange cartoons). (G) The electrostatic surface potential of the bottom side of the E-loop. The dashed lines between (F) and (G) show an electrostatically complementary patch for interaction. (H) Electrostatic surface potential of two neighbouring MCP within a capsomer showing complementarity between the two interacting faces of subunits A and B.

[0059] Figure 8 - Genetic validation of the structure of the EcCIEDL933 capsid. (A) Representation of the residues involved in the formation of salt bridges in EcCIEDL933 (right) and the corresponding residues in HK97, together with the representation of their electrostatic potential. (B) HK97 capsid mutagenesis affected phage capsid formation. The strain carrying an HK106 prophage mutant in its capsid gene was complemented with the pBAD18 empty vector (-) or different versions of the HK97 capsid gene. Samples were induced with 2 pg / mL MC and 0.02% arabinose. The resulting filtered lysates were tested for phage titration in E. coli strain 594 expressing the WT HK97 capsid gene. Values are presented as means for the plaque-forming units (PFU) per milliliter of lysates. Error bars indicate the standard deviation. A one-way ANOVA with Dunnett’s multiple comparisons test was used to compare the data between samples with the WT HK97 capsid and the other samples after log10transformation, ns: P > 0.05. **: P ≤ 0.01. ****: P ≤ 0.0001. n = 4 independent samples. (C) EcCIEDL933 mutagenesis abolished EcCIEDL933 transfer. Derivative strains lysogenic for HK106 and carrying different versions of the EcCIEDL933 capsid gene were MC-induced, and the transfer of the WT and mutant islands was analysed. Values are presented as means for the colonyforming units (CFU) per milliliter of lysates. Error bars indicate the standard deviation. A oneway ANOVA with Dunnett’s multiple comparisons test was used to compare the data between samples with the WT EcCIEDL933 capsid and the other samples after log10transformation. ****: P ≤ 0.0001. n = 4 independent samples.Figure 11 - Formation of chimeric phage particles with capsids from phage lambda combined with tails from phage 80 and vice versa. Bar graph showing the number of lysogens produced in two different E. coll strains, a lamb mutant (grey bars) and a fhuA mutant (black bars) for chimeric phages produced by mixing tail-less capsids from phage lambda or 80 with tails from phage lambda or 80.

[0060] Figure 12 - KpCIDSM30104 uses the excess of tails produced after induction of the HK022 prophage. Tenfold dilutions of the HK022 lysate (maximum concentration: 106PFU / mL) were mixed with KpCIDSM30104 (108particles / mL) or LB (as a control). The mixed lysates were then used to infect E. coli (A), and the number of plaques obtained was quantified (B). A t-test was used to compare the data after log10transformation, ns: P > 0.05. (C) KpCIDSM30104 transfer obtained with the mix that contained the highest concentration of phage lysate (106PFU / mL).

[0061] Figure 13 - Purification of EcCIEDL933 via ion-exchange chromatography. (A) After initial purification by CsCI density gradient centrifugation, EcCIEDL933 virions were subjected to anionic exchange chromatography on HiTrap Q HP Cytvia column to remove the excess unbound tails of the helper phage HK107. The chromatography was conducted at pH 8.4 in a gradient of buffer B containing 2M NaAc relative to buffer A devoid of NaAc, resulting in two distinct peaks.

[0062] Figure 14 - KpCIDSM30104 alters the tail compatibility of EcCIGN02175. Antibiotic resistance markers tetA and cat were introduced into cf-PICI KpCIDSM30104 and cf-PICI EcCIGN02175, respectively. An E. coli strain C1a harbouring prophage HK022 and cf-PICI EcCIGN02175, and an E. coli strain C1a harbouring prophage HK022, cf-PICI EcCIGN02175, and cf-PICI KpCIDSM30104, were independently cultured overnight. Mitomycin C was added to a induce prophage and cf-PICI mobilisation. Following induction, culture lysates were harvested and plated onto LB agar supplemented with either tetracycline or chloramphenicol. Transductants were enumerated as colony-forming units (CFU) and expressed as CFU per milliliter of cf-PICI lysate.

[0063] Figure 15 - EcCIGN02175 reciprocally alters the tail compatibility of KpCIDSM30104. A derivative of E. coll strain C1a harbouring prophage HK022, EcCIGN02175, and KpCIDSM30104 was constructed in which the adaptor and connector genes of KpCIDSM30104 were deleted. Transfer of both KpCIDSM30104 and EcCIGN02175 was abolished. Supplementation of the resulting lysates with phage HK106 tails, which specifically interact with the EcCIGN02175 adaptor, restored the transfer of both EcCIGN02175 andKpCIDSM30104. (left) KpCIDSM30104 transfer, (right) EcCIGN02175 transfer. Values are presented as means of colony-forming units (CFU) per milliliter of cf-PICI donor lysates. WT: Wild-type; Mutant: adaptor and connector deletion mutant.

[0064] Figure 16 - Electron microscopy pictures evidence of tail-first mechanism. (A) Negative staining image of HK022 tails attached to E.coli c1a. (B) Negative staining image of HK022 tails with attached empty KpCIDSM30104 capsids upon successful DNAtransfer. Both images have a 100 nm scale. The images clearly show that isolated tails are able to attach to bacterium (A) and act as antennas to recruit tail-less capsids (B), evidence of the tail-first mechanism described herein.

[0065] DETAILED DESCRIPTION

[0066] Definitions

[0067] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Singleton, et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 20 ED., John Wiley and Sons, New York (1994), and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY, Harper Perennial, NY (1991) provide the skilled person with a general dictionary of many of the terms used in this disclosure. The meaning and scope of the terms should be clear; however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary.

[0068] This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0069] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognise. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments describedherein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0070] The headings provided herein are not limitations of the various aspects or embodiments of this disclosure.

[0071] As used herein, the term "capable of' when used with a verb, encompasses or means the action of the corresponding verb. For example, "capable of interacting" also means interacting, "capable of connecting" also means connects, "capable of binding" also means binds, “capable of assembling” also means assembles, and "capable of specifically targeting..." also means specifically targets.

[0072] Numeric ranges are inclusive of the numbers defining the range. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure.

[0073] As used herein, the articles "a" and “an” may refer to one or to more than one (e.g. to at least one) of the grammatical object of the article. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting.

[0074] “About” may generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. Preferably, the term “about” shall be understood herein as plus or minus (±) 5%, preferably ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, of the numerical value of the numberwith which it is being used.The term "consisting of' refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the invention.

[0075] As used herein the term "consisting essentially of' refers to those elements required for a given invention. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that invention (i.e. inactive or non-immunogenic ingredients).

[0076] Embodiments described herein as “comprising” one or more features may also be considered as disclosure of the corresponding embodiments “consisting of’ and / or “consisting essentially of’ such features.

[0077] Amino acids are referred to herein using the name of the amino acid, the three-letter abbreviation or the single letter abbreviation. The term “protein", as used herein, includes proteins, polypeptides, and peptides. As used herein, the term “amino acid sequence” is synonymous with the term “polypeptide” and / or the term “protein”. In some instances, the term “amino acid sequence” is synonymous with the term “peptide”. In some instances, the term “amino acid sequence” is synonymous with the term “enzyme”. The terms "protein" and "polypeptide" are used interchangeably herein. In the present disclosure and claims, the conventional one-letter and three-letter codes for amino acid residues may be used. The 3-letter code for amino acids as defined in conformity with the IUPACIUB Joint Commission on Biochemical Nomenclature (JCBN). It is also understood that a polypeptide may be coded for by more than one nucleotide sequence due to the degeneracy of the genetic code.

[0078] A “fragment” of a polypeptide typically comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97% or more of the original polypeptide. A fragment may be continuous or discontinuous. A discontinuous fragment is one which is lacking at least one region of continuous amino acids from within the full-length protein, such that the discontinuous fragment has at least one gap or break in the full-length sequence. A discontinuous fragment of the invention comprises at least two regions, at least three regions, at least four regions, at least five regions, at least six regions, at least seven regions, at least eight regions, at least nine regions, at least ten regions, or more regions of continuous amino acid sequence from the full-length protein which are separated in the full-length protein, but which form a single polypeptide in the discontinuous fragment.

[0079] A “variant” amino acid sequence has substantial homology or substantial similarity to a reference amino acid sequence (or a fragment thereof). A amino acid sequence or fragment thereof is “substantially homologous” (or “substantially identical”) to a reference sequence if, when optimally aligned (with appropriate amino acid insertions or deletions) with the other amino acid there is amino acid sequence identity in at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99% or more, up to 100% of the amino acids. Methods for homology determination of amino acid sequences are known in the art. Typically a variant polypeptide of the invention retains the function or activity of the full-length polypeptide. A variant may have a higher level of sequence identity over specific motifs and / or domains (e.g. at least 70% sequence identity or more, such as at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more %), and a lower level of sequence identity over its full length (e.g. at least 20% sequence identity or more, such as at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more) compared with a reference amino acid sequence.

[0080] A variant polypeptide may be one in which amino acid residues from one species are substituted for the corresponding residue in another species, either at the conserved or nonconserved positions. Variants of DNMTs disclosed herein may be produced and used in the present invention. Following the lead of computational chemistry in applying multivariate data analysis techniques to the structure / property-activity relationships [see for example, Wold, et al. Multivariate data analysis in chemistry. Chemometrics-Mathematics and Statistics in Chemistry (Ed.: B. Kowalski); D. Reidel Publishing Company, Dordrecht, Holland, 1984 (ISBN 90-277-1846-6] quantitative activity-property relationships of DNMTs can be derived using well-known mathematical techniques, such as statistical regression, pattern recognition and classification [see for example Norman et al. Applied Regression Analysis. Wiley-Interscience; 3rd edition (April 1998) ISBN: 0471170828; Kandel, Abraham et al. Computer-Assisted Reasoning in Cluster Analysis. Prentice Hall PTR, (May 11, 1995), ISBN: 0133418847; Krzanowski, Wojtek. Principles of Multivariate Analysis: A User's Perspective (Oxford Statistical Science Series, No 22 (Paper)). Oxford University Press; (December 2000), ISBN: 0198507089; Witten, Ian H. et al Data Mining: Practical Machine Learning Tools and Techniques with Java Implementations. Morgan Kaufmann; (October 11, 1999), ISBN: 1558605525; Denison David G. T. (Editor) et al Bayesian Methods for Nonlinear Classification and Regression (Wiley Series in Probability and Statistics). John Wiley & Sons; (July 2002), ISBN: 0471490369; Ghose, Arup K. et al. Combinatorial Library Design and Evaluation Principles, Software, Tools, and Applications in Drug Discovery. ISBN: 0-8247-0487-8], The properties of a DNMT can be derived from empirical and theoretical models (for example, analysis of likely contact residues or calculated physicochemical property) of the DNMT sequence, functional and three-dimensional structures and these properties can be considered individually and in combination.

[0081] Amino acid residues at non-conserved positions may be substituted with conservative or non-conservative residues. In particular, conservative amino acid replacements are contemplated.

[0082] A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acidresidues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, or histidine), acidic side chains (e.g., aspartic acid or glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, or cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, or tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, or histidine). Thus, if an amino acid in a polypeptide is replaced with another amino acid from the same side chain family, the amino acid substitution is considered to be conservative. The inclusion of conservatively modified variants in a DNMT of the invention does not exclude other forms of variant, for example polymorphic variants, interspecies homologs, and alleles.

[0083] “Non-conservative amino acid substitutions” include those in which (i) a residue having an electropositive side chain (e.g., Arg, His or Lys) is substituted for, or by, an electronegative residue (e.g., Glu or Asp), (ii) a hydrophilic residue (e.g., Ser or Thr) is substituted for, or by, a hydrophobic residue (e.g., Ala, Leu, Ile, Phe or Val), (iii) a cysteine or proline is substituted for, or by, any other residue, or (iv) a residue having a bulky hydrophobic or aromatic side chain (e.g., Val, His, Ile or Trp) is substituted for, or by, one having a smaller side chain (e.g., Ala or Ser) or no side chain (e.g., Gly).

[0084] As used herein, the terms “polynucleotides”, "nucleic acid" and "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid or an analogue thereof. The nucleic acid can be either single-stranded or double-stranded. A single-stranded nucleic acid can be one nucleic acid strand of a denatured double- stranded DNA Alternatively, it can be a single-stranded nucleic acid not derived from any double-stranded DNA. In one aspect, the nucleic acid can be DNA. In another aspect, the nucleic acid can be RNA Suitable nucleic acid molecules are DNA, including genomic DNA or cDNA. Other examples of nucleic acid molecules are RNA, including siRNA, shRNA, and antisense oligonucleotides.

[0085] Unless otherwise indicated, any nucleic acid sequences are written left to right in 5' to 3' orientation.

[0086] The polynucleotides of the present invention may be prepared by any means known in the art. For example, large amounts of the polynucleotides may be produced by replication in a suitable host cell. The natural or synthetic DNA fragments coding for a desired fragment will be incorporated into recombinant nucleic acid constructs, typically DNA constructs, capable of introduction into and replication in a prokaryotic or eukaryotic cell. Usually, the DNA constructs will be suitable for autonomous replication in a unicellular host, such as yeast or bacteria, but may also be intended for introduction to and integration within the genome of a cultured insect, mammalian, plant or other eukaryotic cell lines.The polynucleotides of the present invention may also be produced by chemical synthesis, e.g. by the phosphoramidite method or the tri-ester method and may be performed on commercial automated oligonucleotide synthesisers. A double-stranded fragment may be obtained from the single stranded product of chemical synthesis either by synthesising the complementary strand and annealing the strand together under appropriate conditions or by adding the complementary strand using DNA polymerase with an appropriate primer sequence.

[0087] In view of the degeneracy of the genetic code, considerable sequence variation is possible among the polynucleotides of the present invention. Degenerate codons encompassing all possible codons for a given amino acid are set forth below:

[0088] Amino Acid Codons Deqenerate Codon

[0089] Cys TGC TGT TGY

[0090] Ser AGC AGT TCA TCC TCG TCT WSN

[0091] Thr ACAACCACGACT ACN

[0092] Pro CCACCC CCG CCT CCN

[0093] Ala GCAGCC GCG GCT GCN

[0094] Gly GGAGGC GGG GGT GGN

[0095] Asn AAC AAT AAY

[0096] Asp GAC GAT GAY

[0097] Glu GAAGAG GAR

[0098] Gln CAA CAG CAR

[0099] His CAC CAT CAY

[0100] Arg AGAAGG CGACGC CGG CGT MGN

[0101] Lys AAAAAG AAR

[0102] Met ATG ATG

[0103] Ile ATA ATC ATT ATH

[0104] Leu CTA CTC CTG CTT TTA TTG YTN

[0105] Val GTA GTC GTG GTT GTN

[0106] Phe TTC TTT TTY

[0107] Tyr TAC TAT TAY

[0108] Trp TGG TGG

[0109] Ter TAA TAG TGA TRR

[0110] Asn / Asp RAY

[0111] Glu / Gin SAR

[0112] Any NNNOne of ordinary skill in the art will appreciate that flexibility exists when determining a degenerate codon, representative of all possible codons encoding each amino acid. For example, some polynucleotides encompassed by the degenerate sequence may encode variant amino acid sequences, but one of ordinary skill in the art can easily identify such variant sequences by reference to the amino acid sequences of the present invention.

[0113] A “variant” nucleic acid sequence has substantial homology or substantial similarity to a reference nucleic acid sequence (or a fragment thereof). A nucleic acid sequence or fragment thereof is “substantially homologous” (or “substantially identical”) to a reference sequence if, when optimally aligned (with appropriate nucleotide insertions or deletions) with the other nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more % of the nucleotide bases. Methods for homology determination of nucleic acid sequences are known in the art. A variant nucleic acid sequence may have a higher level of sequence identity over specific regions encoding particular motifs and / or domains (e.g. at least 70% sequence identity or more, such as at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more %), and a lower level of sequence identity over its full length (e.g. at least 20% sequence identity or more, such as at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more) compared with a reference nucleic acid sequence.

[0114] Alternatively, a “variant” nucleic acid sequence is substantially homologous with (or substantially identical to) a reference sequence (or a fragment thereof) if the “variant” and the reference sequence they are capable of hybridising under stringent (e.g. highly stringent) hybridisation conditions. Nucleic acid sequence hybridization will be affected by such conditions as salt concentration (e.g. NaCI), temperature, or organic solvents, in addition to the base composition, length of the complementary strands, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. Stringent temperature conditions are preferably employed, and generally include temperatures in excess of 30°C, typically in excess of 37°C and preferably in excess of 45°C. Stringent salt conditions will ordinarily be less than 1000 mM, typically less than 500 mM, and preferably less than 200 mM. The pH is typically between 7.0 and 8.3. The combination of parameters is much more important than any single parameter.

[0115] Methods of determining nucleic acid percentage sequence identity are known in the art. By way of example, when assessing nucleic acid sequence identity, a sequence having a defined number of contiguous nucleotides may be aligned with a nucleic acid sequence (having the same number of contiguous nucleotides) from the corresponding portion of a nucleic acid sequence of the present invention. Tools known in the art for determining nucleic acid percentage sequence identity include Nucleotide BLAST (as described below).One of ordinary skill in the art appreciates that different species exhibit “preferential codon usage”. As used herein, the term “preferential codon usage” refers to codons that are most frequently used in cells of a certain species, thus favouring one or a few representatives of the possible codons encoding each amino acid. For example, the amino acid threonine (Thr) may be encoded by ACA, ACC, ACG, or ACT, but in mammalian host cells ACC is the most commonly used codon; in other species, different codons may be preferential. Preferential codons for a particular host cell species can be introduced into the polynucleotides of the present invention by a variety of methods known in the art. Introduction of preferential codon sequences into recombinant DNAcan, for example, enhance production of the protein by making protein translation more efficient within a particular cell type or species.

[0116] A “fragment” of a polynucleotide of interest comprises a series of consecutive nucleotides from the sequence of said full-length polynucleotide. By way of example, a “fragment” of a polynucleotide of interest may comprise (or consist of) at least 30 consecutive nucleotides from the sequence of said polynucleotide (e.g. at least 35, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 1750, 2000, 2100, 2200, 2300 or more consecutive nucleic acid residues of said polynucleotide). Typically, a fragment as defined herein retains the same function as the full-length polynucleotide.

[0117] When applied to a nucleic acid sequence, the term “isolated” denotes that the polynucleotide sequence has been removed from its natural genetic milieu and is thus free of other extraneous or unwanted coding sequences (but may include naturally occurring 5' and 3' untranslated regions such as promoters and terminators) and is in a form suitable for use within genetically engineered protein production systems. Such isolated molecules are those that are separated from their natural environment. In the context of the invention, an isolated nucleic acid is one which has been separated from one or more of the reagents used in its production according to methods of the invention; one which has been separated from the other nucleic acid sequences synthesised in the same iteration of the method and / or one which has been separated from the one or more units on which it was synthesised.

[0118] When applied to a polypeptide sequence, such as the tail or capsid of a phage, phage satellite or phage-related element, the term “isolated” denotes that the polypeptide, tail or capsid has been removed from its natural milieu and is thus substantially free of other extraneous or unwanted polypeptides, such as tails and is in a form suitable for use in ex vivo and / or in vivo methods. Such isolated polypeptides, tails or capsids are those that are separated from their natural environment. In the context of the invention, an isolated tail or tail-less capsid is one which has been separated from one or more of the reagents used in its production according to methods of the invention.The terms “decrease”, "reduced", "reduction", or "inhibit" are all used herein to mean a decrease by a statistically significant amount. The terms "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reduction" or "inhibition" encompasses a complete inhibition or reduction as compared to a reference level. " Complete inhibition" is a 100% inhibition (i.e. abrogation) as compared to a reference level.

[0119] The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. The terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 25%, at least 50% as compared to a reference level, for example an increase of at least about 50%, or at least about 75%, or at least about 80%, or at least about 90%, at least about 95%, or at least about 98%, or at least about 99%, or at least about 100%, or at least about 250% or more compared with a reference level, or at least about a 1.5-fold, or at least about a 2-fold, or at least about a 2.5-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 1.5-fold and 10-fold or greater as compared to a reference level.

[0120] As used herein, the term “sample” refers to a sample of biological materials (cells, tissue, fluid, etc.). Said material may be obtained from a eukaryotic or prokaryotic organism. Typically, the sample is from a eukaryotic multicellular organism, such as an animal or plant. The sample may be from a mammal, particularly a human. The mammal, particularly a human may be an adult or a juvenile, male or female. Thus a sample may be obtained from a subject, and particularly in the case of a diagnostic application, from a subject suspected of having or at risk of having a medical condition. The sample may be any suitable biological material, for example blood, plasma, saliva, serum, sputum, urine, cerebrospinal fluid, sweat, synovial fluid, cells, a cellular extract, a tissue sample, a tissue biopsy, a stool sample and the like. Typically, the sample is a biological fluid, such as blood, plasma, saliva, serum, sputum, urine, cerebrospinal fluid, sweat, synovial fluid, preferably a blood sample. The precise biological sample that is taken from the individual may vary, but the sampling preferably is minimally invasive and is easily performed by conventional techniques. The sample may be a whole blood sample, a purified peripheral blood leukocyte sample or a cell type sorted leukocyte sample, such as a sample of the individual’s neutrophils. For non-medical applications, samples may be environmental materials, such as soil samples, water samples, swabs or similar materials.The term “pharmaceutically acceptable” as used herein means approved by a regulatory agency of the Federal or a state government, or listed in the U. S. Pharmacopeia, European Pharmacopeia or other generally recognised pharmacopeia.

[0121] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto.

[0122] Phage, phage satellites and phage-related elements

[0123] Genetic variation of bacteria and archaea can be achieved through mutations, rearrangements and horizontal gene transfers and recombinations. Increasing genome sequence data have demonstrated that, besides the core genes encoding house-keeping functions such as essential metabolic activities, information processing, and bacterial structural and regulatory components, a vast number of accessory genes encoding antimicrobial resistance, toxins, and enzymes that contribute to adaptation and survival under certain environmental conditions are acquired by horizontal gene transfer of mobile genetic elements (MGEs). Mobile genetic elements are a heterogeneous group of molecules that include plasmids, bacteriophages, genomic islands, chromosomal cassettes, pathogenicity islands, and integrative and conjugative elements. Genomic islands are relatively large segments of DNA ranging from 10 to 200 kb often integrated into tRNAgene clusters flanked by 16-20 bp direct repeats. They are recognised as discrete DNA segments acquired by horizontal gene transfer since they can differ from the rest of the chromosome in terms of GC content (%G+C) and codon usage.

[0124] As described herein, the present invention relates to chimeric particles comprising elements from mobile genetic elements (MGE), particularly from bacteriophages (phage), phage satellites or phage-related elements. The chimeric particles of the invention comprise elements from two different phage, phage satellites or phage-related elements, as described herein. In some embodiments, chimeric particles of the invention comprise elements from two different phage or phage satellites, as described herein.

[0125] Phage

[0126] Bacteriophage (also referred to interchangeably as phages) are viruses that infect and replicate in bacterial cells.

[0127] An individual phage particle comprises a nucleic acid, which can be either DNA or RNA, which is encapsulated within a capsid. Extending from the capsid is the tail structure, which mediate delivery of the phage’s nucleic acid into the host cell. Phages are typically species-specific, usually only infecting a single bacterial species or even specific strains within a species.Databases of phages are publicly available, including PhageScope

[0128]

[0129] ( ), PhageDive ( ) and the Actinbacteriophage database (

[0130]

[0131] ). It is therefore within the routine practice of one of ordinary skill in the art to characterise a MGE as a phage, and also to identify and select suitable phages for using in the present invention.

[0132] A phage according to the invention may be selected from the order Caudovirales. This order includes the families Podoviridae, Siphoviridae and Myoviridae. Accordingly, a phage according to the invention may be selected from the order Caudovirales, optionally from the family Podoviridae, Siphoviridae or Myoviridae. Furthermore, a phage according to the invention may be selected from the order Caudovirales, optionally from the family Podoviridae, Siphoviridae, Myoviridae, Ackermannviridae or Herelleviridae, further optionally from the family Podoviridae, Siphoviridae or Myoviridae.

[0133] The Caudovirales order and the families Podoviridae, Siphoviridae, Myoviridae, Ackermannviridae or Herelleviridae have been reclassified by the International Committee on Taxonomy of Viruses (ICTV) using genome-based taxonomy. All tailed bacteriophages are classified as Caudoviricetes, non-limiting examples of Caudoviricetes families include Demerecviridae, Drexlerviridae, Siphoviridae-like families. Whether using the traditional nomenclature, or the new genome-based groupings, one of ordinary skill in the art would readily be able to determine whether a phage is a tailed phage (i.e. a member of the Caudovirales order or Caudoviricetes) and so relevant to the present invention. Standard techniques for the visualisation and / or classification of phage are well-known in the art, and could be selected and used by a skilled person without undue burden.

[0134] By way of non-limiting example, a phage may be selected from the group consisting of: (i) a Siphoviridae phage; (ii) a Myoviridae phage; (iii) a Podoviridae phage; and (iv) any other phage type.

[0135] Non-limiting examples of Siphoviridae phage include: E. coll phages, such as lambda phage, 80 phage, T 1 phage and T5 phage; Staphylococcus aureus phages, such as φ11 and 80 α; Salmonella enterica phages such as BTP1; and Lactococcus lactis phages such as TP901-1.

[0136] Non-limiting examples of Myoviridae phage include: E. coll phages such as T4, P1, P2, and MuT2; Bacillus subtilis phages such as SPO1; and S. aureus phages such as ΦK, Φ812 and ΦMR11.

[0137] Non-limiting examples of Podoviridae phage include: E. coll phages such as T7; Salmonella enterica phages such as P22; B. subtilis phages such as phi29; Streptococcus pneumoniae phages such as CP-1; and S. aureus phages such as Φ44RR2.8t.Non-limiting examples of other phages that may be used in the present invention include: E. coli phages such as M13, MS2, and PhiX174; Pseudomonas syringae phages such as Φ6; Vibrio cholerae phages such as autolykivirus; Acinetobacter baumannii phages such as ΦAb1; PRD1 phage; and cyanophage.

[0138] Phage satellites

[0139] Bacteriophage satellites (phage satellites) are genetic elements that couple their life cycle to that of helper phages they parasitise, interfering with phage packaging through the production of small capsids, where only satellites are packaged. The capsids of exemplified cf-PICIs have diameters in the range of diameter of between about 30 nm to about 70 nm, with the cf-PICI having a capsid of 47.5 nm in diameter. By comparison, phage capsids typically range from between about 30 nm to about 160 nm in diameter.

[0140] Phage satellites are well-known in the art, as are methods for their identification and characterisation. By way of non-limiting example, such methods are described by Moura de Sousa et al (Nucleic Acid Research (2023) 51(6):2759–2777, which is co-authored by the present inventors; and Ibarra-Chavez et al FEMS Microbiology Reviews (2021) 45(6): 1-20, each of which are incorporated by reference herein. Sequences of phage satellites can be readily obtained through publicly accessible databases, such as the NCBI non-redundant RefSeq database as described in Moura de Sousa et al. Other examples of databases of phage and phage satellites include PhageScope (https: / / phaqescope.deepomics.org / ) and PhageDive (https: / / phaqedive.com / ). It is therefore within the routine practice of one of ordinary skill in the art to characterise a MGE as a phage satellite, or class thereof, and also to identify suitable phage satellites for using in the present invention.

[0141] In most classes of phage satellites, the satellite-sized capsids are composed of phage proteins. In a recently-identified class of phage satellites, capsid-forming phage-inducible chromosomal islands (cf-PICIs), the cf-PICI genome encodes all the proteins required for both the production of small-sized capsids and the exclusive packaging of the cf-PICIs into these capsids.

[0142] Non-limiting examples of phage satellites include capsid-forming PICIs (cf-PICIs), phage inducible chromosomal islands (PICIs), P4-like satellites and PICI-like elements (PLEs), which are described in more detail herein.

[0143] Chimeric particles of the invention may comprise a capsid from any phage satellite, such as those described and / or exemplified herein. In particular, chimeric particles of the invention may comprise a capsid from any capsid-forming PICI (cf-PICI), phage inducible chromosomal islands (PICI), P4-like satellite, or PICI-like element (PLE), such as those described and / or exemplified herein. As described herein, it is within the routine practice of one of ordinary skill in the art to characterise a phage satellite as a cf-PICI, PICI, P4-likesatellite or PLE, and also to identify suitable cf-PICIs, PICIs, P4-like satellites and PLEs for using in the present invention. These classes of phage satellites are discussed further herein.

[0144] Phage-inducible chromosomal islands

[0145] Phage-inducible chromosomal islands (PICIs) are small (approx. 10-15 kb), chromosomally integrated elements that are extremely widespread in nature, being present in more than 200 species, with many strains containing two or more of these elements. PICIs are intimately related to certain temperate (helper) phages, whose life cycles they parasitise. In the presence of active helper phages, and once induced, PICIs replicate extensively, then excise from the bacterial chromosome and are efficiently packaged into infectious particles composed of helper phage virion proteins, which mediate the high intra-species transfer of these genetic elements.

[0146] PICI include the Staphylococcus aureus pathogenicity islands (SaPI), which have been extensively studied, as well as numerous other elements present in both diderm and monoderm bacteria. PICI have a conserved genetic organisation and five core components found in almost all known elements: (i) an integrase; (ii) a regulation module (homolog to alpA, merR or sf / ); (Hi) a primase-replicase module; (iv) a capsid morphogenesis module (more frequent in PICI from Proteobacteria), encoding a protein that is thought to modify the morphology of the hijacked capsids to block the encapsidation of phage DNA; and (v) a small terminase subunit, which is responsible for redirecting the packaging of the capsid to the satellite’s DNA. Other accessory genes may also be encoded by PICI (notably between the integrase and the regulation or the primase-replication module, or after the terS homolog), PICI typically do not encode other phage-like structural or lysis genes.

[0147] Any PICI may be used in the present invention. Wherein a PICI is not a cf-PICI, use of a PICI may drive use of a phage capsid in chimeric particles of the invention, relying on the natural mechanisms of the PICI to encapsidate its own genome. It is within the routine practice of one of ordinary skill in the art to identify and select suitable PICIs for use in the present invention.

[0148] A PICIs used in the present invention may be selected from the PICIs identified in File S2 of de Sousa et al. (2023). Nucleic Acids Res 51, 2759–2777. By way of non-limiting example, a PICI may be selected from the group consisting of EcCI11368.1, EcCIIHE3034, ECCIRM13514, EcCIRM12579, EcCIATCC_25922, EcCI042, PcCIPCC221, EcCIDi14, SbCISb277, PmCIOH1905, PhaCIATCC43949, EcCICFT073, EcCI11128, SAPI1, LICIKF147, LICIA76-1, SaPlmw2, SAPI2, SpnCITaiwan-0.2, SpnCITaiwan-0.03, SpnCI-A45-1.9, SaPIbovI, LICISK11, SpnCITCH8341-0.25, SpnCIINV104-1.06, EfCIV583, MG1363-1 and LICI-CV56-1, all of which are described in Table S1 of de Sousa et al. (2023). Nucleic Acids Res 51, 2759–2777.Capsid-forming PICIs

[0149] Capsid-forming PICIs (cf-PICIs) are a family of PICIs that encode all the proteins required not only for the production of PICI-sized capsids but also for the exclusive packaging of the cf-PICIs into these capsids. Although cf-PICI can form capsids, they are incapable of forming viable phage particles because they lack other structural genes that they hijack from the helper phage, e.g. holins and tail-associated proteins.

[0150] Five core components of cf-PICI are homologous or analogous to the five core components of PICI (as described herein). Some accessory genes that can be present in PICI may also be present in cf-PICI, such as a nuclease (HNH) which is involved in phage head morphogenesis (and DNA packaging), and a head decoration module (a serine protease). Without being bound by theory, it is believed that that some of these accessory genes might be used for the modification and stabilisation of capsid morphology.

[0151] Cf-PICI differ from other PICI in that cf-PICI comprise several core components of which are not present in other PICI. In particular, cf-PICI comprise genes involved in the attachment of the capsid to the parasitised tails. In some cf-PICI, these genes encode a headtail adaptor and / or a head-tail connector. Further, in some cf-PICI, these genes encode, a portal protein, a head-tail adaptor and / or a head-tail connector. Alternatively, or in addition, these cf-PICI distinguishing genes can encode a large terminase protein (terL)

[0152] In some preferred embodiments, chimeric particles of the invention comprise a capsid from or derived from a cf-PICI. Any cf-PICI may be used in the present invention. It is within the routine practice of one of ordinary skill in the art to identify and select suitable cf-PICIs for use in the present invention.

[0153] The cfPICIs used in the present invention may be selected from the cfPICIs identified in File S2 of de Sousa et al. (2023). Nucleic Acids Res 51, 2759–2777. Byway of non-limiting example, a cfPICI may be selected from the group consisting KpCIDSM30104, EcCIGN02175, EcCIEDL, EcCISMS-3-5, EcCIPNUSAE044409, SeCIDerby, YaCI159, SfCI301, SfCI8401, ECCIIAI39, CfCICFNIH4, EcCIEC11-7286, EcCIEDIa, EcCIWW223, EpCIETW41, PgCIFDAARGOS.186, SdCICCFSAN010956, SeCIFDA336426-1, PmCIATCC29906, ECCIEO709, EcCIRM 10386, KvCIGJ3, EcCICFSAN002236, EcCID8, EcCIRM 10042, CpCITV06, EcCIHUST159, SeCI08-1209, EcCI392917, SeCIKentucky, GaCISCGC, GaCIWKBI, KpCIAR.0148, EcCIEDL933, EcCI144, EcCIPA40, SeCI7830, EcCIST130, KpCIKPNOI, EcCIPSUO103, KoCICAV175, XnCIATCC1906, EcCI315650, B..kocchi. BDGP4, B.cereus. BAG6X1-2, S.saprophyticus. CCUG38042, C.botulinum. B. Eklund.17B, S.pettenkoferi.589, S.haemolitycus. S167, S. equorum. DSM15097, S.aureus. VET0180R, S.xylosus. HKUOPL8, C.beijerinckii. WB53, S.arlettae.lOV5, S.. aureus. C0673, E.durans.4928STDY7071318, S.warneri. DE0454, L.rhammosus. GG,B.thuringiensis. BGSC.4W1.4W1, L.casei. Lc705, C.sporogenes.87-0535, S.hominis. SNUC.5746, L.casei. BL23, all of which are described in Table S1 of de Sousa et al. (2023). Nucleic Acids Res 51, 2759–2777. Preferably, a cf-PICI may be selected from the group consisting of KpCIDSM30104, EcCIGN02175, and EcCIEDL.

[0154] P4-Hke satellites

[0155] The P4 satellite is among the best studied phage satellites. The P4 satellite physically constrains P2 capsids to encapsidate its own DNA. The P4-like family of satellites contains seven very conserved components: (i) an integrase; (ii) Psu; (iii) Delta; (iv) Sid; (v) a regulatory protein, typically homologous to AlpA, MerR or Stl; (vi) Ash (also called ε); and (vii) α, a protein with primase and helicase activities.

[0156] Psu, Delta and Sid are involved in the hijacking of the capsid of the P2 helper phage. Ash (ε), inactivates the repressor of the helper phage, causing its induction. The α protein with primase and helicase activities is required for P4 replication.

[0157] Any P4-like satellite may be used in the present invention. It is within the routine practice of one of ordinary skill in the art to identify and select suitable P4-like satellites for use in the present invention.

[0158] A P4-like satellite used in the present invention may also be selected from the P4-like satellites identified in File S2 of de Sousa et al. (2023). Nucleic Acids Res 51, 2759–2777.

[0159] For example, a P4-like satellite used in the present invention may be selected from the group consisting of the P4-like satellites identified in any of Lelliottia amnigena, Escherichia coli, Shigella boydii, Klebsiella pneumoniae, Salmonella enterica, Klebsiella variicola, Klebsiella sp., Shimwellia blattae, Escherichia albertii, Enterobacter cloacae, Enterobacter hormaechei, Citrobacter freundii, Cronobacter malonaticus, Escherichia fergusonii, Buttiauxella sp., Enterobacteriaceae bacterium, Citrobacter werkmanii, Kluyvera intermedia, Escherichia marmotae, Enterobacter sp., Cedecea lapagei, Klebsiella oxytoca, Raoultella ornithinolytica, Cronobacter muytjensii, Salmonella sp., Kosakonia cowanii, Enterobacter roggenkampii, Kosakonia sp., Metakosakonia sp., Citrobacter sp., Klebsiella quasipneumoniae, Citrobacter portucalensis, Klebsiella michiganensis, Klebsiella aerogenes, Kosakonia sacchari, Cronobacter sakazakii, Enterobacter kobei, Raoultella planticola, Atlantibacter hermannii, Pantoea vagans, Pantoea alhagi, Mixta calida, Erwinia billingiae, Pantoea sp., Erwinia sp., Pantoea rwandensis, Pantoea ananatis, Tatumella ptyseos, Edwardsiella sp., Edwardsiella piscicida, Edwardsiella tarda, Edwardsiella anguillarum, Hafnia sp., Hafnia alvei, Pectobacterium wasabiae, Pectobacterium carotovorum, Pectobacterium atrosepticum, Pectobacterium polaris, Pectobacterium parmentieri, Serratia sp., Serratia marcescens, Yersinia enterocolitica, Yersinia aldovae, Yersinia ruckeri, Serratia fonticola, Serratia plymuthica, Yersinia sp., Yersinia massiliensis, Serratia liquefaciens, Yersiniafrederiksenii, Serratia nematodiphila or Yersinia similis, as described in the Supplementary Table S2 of Moura de Sousa et al. (2022) Phil. Trans. R. Soc. B 377: 20200475. In particular, a P4-like satellite used in the present invention may be selected from type A, type B or type C as described in the Results section (a) of Moura de Sousa et al. (2022) Phil. Trans. R. Soc. B 377: 20200475.

[0160] PICI-Hke elements

[0161] PICI-like elements (PLEs) excise from the chromosome and package their genomes by hijacking the phage ICP1. The cost for ICP1 is exacerbated by the acceleration of lysis promoted by PLEs after their packaging, which effectively halts the spread of ICP1 in the population. To date, all confirmed PLEs have been specific to Vibrio cholerae, with some recent putative PLEs described in other Vibrio species (e.g. Vibrio parahemolyticus).

[0162] Markers for PLE include genes encoding proteins with a well-defined role in the PLE lifecycle: an integrase, a gene that represses the capsid morphogenesis of ICP1 (capR), a replication initiation protein (repA), a nickase that hampers the replication of the hijacked phage (nixI), and a gene that accelerates the lysis of the bacterial host cell (lidl). Other markers of PLE include a protein with an HTH binding domain, which was previously described in PLEs, a sigma 70-like factor, a component of the specificity subunit of the bacterial RNA polymerase; and a profile with homology to a cyclin-dependent kinase-activating kinase (MAT1) suggested to be involved in nucleotide excision repair of damaged DNA.

[0163] Any PLE may be used in the present invention. It is within the routine practice of one of ordinary skill in the art to identify and select suitable PLEs for use in the present invention.

[0164] The PLE satellites used in the present invention may be selected from the PLE satellites identified in any of Vibrio cholerae, Vibrio casei, Vibrio alginolyticus or Vibrio vulnificus as described in the File S2 of de Sousa et al. (2023). Nucleic Acids Res 51, 2759–2777. By way of non-limiting example, a P4-like satellite may be selected from the group consisting of PLE1, PLE2, PLE3, PLE4 and PLE5, all of which are described in Table S1 of de Sousa et al. (2023). Nucleic Acids Res 51, 2759–2777.

[0165] Phage-related elements

[0166] In addition to phage and phage satellites, other phage-related elements may be used in the present invention. Such phage-related elements typically have similar properties to phage and phage satellites, in that they will assemble to form a capsid which can associate with a tail to achieve gene transfer to a target cell, particularly bacterial cells.

[0167] Gene transfer agents (GTAs) are an example of a class of phage related elements. GTAs work similarly to phages and satellites. GTAs are phage-like entities that contain arandom piece of the genome of the producing cell. The amount of DNAthat a GTA contains is insufficient to encode the protein components of the particle itself. Instead, structural GTA genes are encoded within the genome of the producing cell. All known GTAs have tailed-phage structures. Released GTA particles can transfer DNA from the producing cell to a recipient cell.

[0168] To-date, four GTAs have been identified: RcGTA in the alphaproteobacterium Rhodobacter capsulatus, Dd1 in the deltaproteobacterium Desulfovibrio desulfuricans, VSH-1 (virus of Serpulina hyodysenteriae) in the spirochaete Brachyspira hyodysenteriae and VTA (voltae transfer agent) in the archaeon Methanococcus voltae. GTAs are described in more detail in Lang et al (Nature Reviews Microbiology (2012) 10:472-482), which is herein incorporated by reference in its entirety.

[0169] Any GTA may be used in the present invention. It is within the routine practice of one of ordinary skill in the art to identify and select suitable GTA for use in the present invention. By way of non-limiting example, a P4-like satellite may be selected from the group consisting of RcGTA, Dd1, VSH-1 and VTA.

[0170] Capsids

[0171] The chimeric particles of the present invention comprise a capsid from a first phage, phage satellite or phage-related element. Such phages, phage satellites and phage-related elements are described herein. Also as described herein, in some preferred embodiments, the capsid is from a cf-PICI, examples of which are described herein.

[0172] The capsid from a first phage, phage satellite or phage-related element as used in the present invention is typically a tail-less capsid. As used herein, the term “tail-less capsid” refers to a capsid which is produced without a tail by a phage, phage satellite or phage-related element, and may be secreted as a tail-less capsid particle by a host bacterial cell. As such, a tail-less capsid may be produced and isolated without interacting with a tail from a phage, phage satellite or phage-related element and may be, as described herein, assembled with at least one isolated tail from a second phage, phage satellite or phage-related element independently.

[0173] By way of non-limiting example, as exemplified herein, a chimeric particle of the invention may comprise a capsid from a first phage, phage satellite or phage-related element selected from the group consisting of KpCIDSM30104, EcCIGN02175, EcCIEDL933, lambda or 80.

[0174] A person of ordinary skill in the art will readily be able to classify the genes within a first phage, phage satellite or phage-related element. Thus, said person of ordinary skill in the art will readily be able to classify the genes within a first phage, phage satellite or phage-related element which encode one or more capsid protein. For example, Figure 1 A herein provides a comparative map of two exemplary cf-PICIs, with the capsid encoding genes identified.The capsid from a first phage, phage satellite or phage-related element is not particularly limited, provided that it is capable of encapsidating a nucleic acid as described herein. For the avoidance of doubt, the particles of the invention are chimeric, and as such the capsid and tail are from different phages, phage satellites and phage-related elements. However, any given phage, phage satellite or phage-related element may be able to provide the capsid or the tail, provided that it does not provide both the capsid and the tail to an individual particle.

[0175] In some embodiments, the capsid from a first phage, phage satellite or phage-related element may be from a first phage, phage satellite or phage-related element infectious to gram-positive bacteria. Alternatively or in addition, the capsid from a first phage, phage satellite or phage-related element may be not have been genetically modified, i.e. it is a wildtype capsid.

[0176] Capsid size of naturally-occurring, phage, phage satellites and phage-related elements is generally dictated by the length of their DNA, as this needs to be packaged and injected into bacterial host. Accordingly, the size of a capsid according to the invention is not particularly limited, provided that it is capable of encapsidating a nucleic acid as described herein. A capsid may have a diameter of between about 30 nm to about 170 nm, such as between about 30 nm to about 160 nm, between about 30 nm to about 150 nm, between about 30 nm to about 125 nm, between about 30 nm to about 100 nm, between about 30 nm to about 90 nm, between about 30 nm to about 80 nm, between about 30 nm to about 70 nm, between about 40 nm to about 70 nm, between about 40 nm to about 60 nm, between about 40 nm to about 50 nm, between about 45 nm to about 65 nm, between about 40 nm to about 55 nm, between about 45 nm to about 55 nm, between about 40 nm to about 50 nm, between about 47 nm to about 60 nm, between about 47 nm to about 55 nm or between about 47 nm to about 50 nm, preferably between about 30 nm and 55 nm, more preferably between about 45 nm to about 55 nm. The size of the capsid of the first phage, phage satellite, or phage-related element of the invention may be configured to only accommodate the nucleic acid molecule to be encapsidated by the capsid, optionally at the exclusion of other nucleic acid molecules, such as the unmodified phage, phage satellite, or phage-related element genome, or the genome of other phages, phage satellites, or phage-related elements, as desired.

[0177] The capsids of phages, phage satellites and phage-related elements are made up of repeats of capsid proteins. Typically, capsid proteins are encoded in an immature form by the genome of a phage, phage satellite or phage-related element, and are then processed to form the mature capsid protein.

[0178] Capsids are typically formed from repeating copies of mature capsid proteins (also referred to as protomers). Non-limiting examples of capsid structures are icosahedral, helicaland complex). Again, the structure and / or symmetry of the capsid is not particularly limited, provided that it is capable of encapsidating a nucleic acid as described herein.

[0179] Mature capsid proteins may form larger repeating units (also known as capsomers), which then assemble to form the mature capsid. By way of example, a capsid may be made up of: pentameric capsomers (also known as pentons), with each penton comprising five mature capsid proteins; hexameric capsomers (also known as hexons), with each hexon comprising six mature capsid proteins; or a combination of pentons and hexons. Capsids with icosahedral symmetry are formed of 12 pentons and a number of hexons, which can vary between classes of phages, phage satellites and phage-related elements.

[0180] By way of non-limiting example, the cf-PICI EcCIEDL933 which is used in the Examples herein comprises a capsid which consists of 240 copies of its mature capsid protein. These 240 copies of the mature capsid protein are arranged into 12 pentons and 30 hexons. The mature capsid protein of EcCIEDL933 is formed by proteolytic cleavage of the capsid protein encoded by the EcCIEDL933 genome.

[0181] A capsid of the first phage, phage satellite, or phage-related element of the invention may be non-enveloped. Capsids of the invention may be produced in and released from bacteria by canonical SOS induction and lysis, therefore resulting in non-enveloped capsids. “Non-enveloped” in the context of capsids refers to capsids which are not lipid-enveloped. In other words, a non-enveloped capsid does not comprise any lipid component.

[0182] The present inventors have elucidated for the first time the structure of a cf-PICI capsid as exemplified in the present application (see Example 10, Figure 10). Interestingly the structure of the capsomers has revealed the presence of a loop, herein referred as a “connector loop”. Without being bound by theory, it is believed that this “connector loop” is at least partially responsible for the symmetry and arrangement of the capsomers, leading to the smaller diameter of the cf-PICI capsid compared with phage capsids. The smaller size of the cf-PICI capsid is only capable of encapsidating the genome of the cf-PICI, typically at the exclusion of other nucleic acid molecules, such as unmodified phage, phage satellite, or phage-related element genome, or the genome of other phages, phage satellites, or phage-related elements, as desired. Therefore, a capsid of the invention may be a cf-PICI capsid, which, by virtue of its size (i.e. diameter), is capable of encapsidating only a nucleic acid molecule of the invention, excluding other nucleic acid molecules such as (but not limited to) the genome of the second phage, phage satellite, or phage-related element.

[0183] Accordingly, the capsid of the first phage, phage satellite, or phage-related element may comprise a connector loop as described in the present application. The connector loop may comprise an amino acid sequence having at least 70% sequence identity, at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least98% sequence identity, at least 99% sequence identity or more to residues 227-248 of SEQ ID NO: 3. The connector loop may consist of an amino acid sequence having at least 70% sequence identity, at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, at least 99% sequence identity with residues 227-248 of SEQ ID NO: 3. The connector loop may comprise residues 227-248 of SEQ ID NO: 3. The connector loop may consist of residues 227-248 of SEQ ID NO: 3.

[0184] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins from KpCIDSM30104, EcCIGN02175 and / or EcCIEDL933, typically wherein said plurality of mature capsid proteins are all from KpCIDSM30104, EcCIGN02175 or EcCIEDL933.

[0185] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 1 to 7. Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 1 to 7.

[0186] Achimeric particle of the invention may comprise a cf-PICI capsid which comprises or consists of a plurality of mature cf-PICI capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 1 to 3. A chimeric particle of the invention may comprise a cf-PICI capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 1 to 3.

[0187] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 1. Achimeric particle of the invention may comprise a capsidwhich comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 1.

[0188] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 2. Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 2.

[0189] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 3. Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 3.

[0190] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 4. Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 4.

[0191] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 5. Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsidprotein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 5.

[0192] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 6. Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 6.

[0193] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 7. Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 7.

[0194] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 1 to 7. In particular, a chimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 1 to 3.

[0195] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of SEQ ID NO: 1.

[0196] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of SEQ ID NO: 2.

[0197] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of SEQ ID NO: 3.Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of SEQ ID NO: 4.

[0198] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of SEQ ID NO: 5.

[0199] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of SEQ ID NO: 6.

[0200] Achimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of SEQ ID NO: 7.

[0201] A capsid from a first phage, phage satellite or phage-related element may be capable of interacting with a tail from a single second phage, phage satellite or phage-related element. Alternatively, a capsid from a first phage, phage satellite or phage-related element may be capable of interacting with the tail from two or more different second phages, phage satellites or phage-related elements

[0202] Tails

[0203] The chimeric particles of the present invention comprise a tail from a second phage, phage satellite or phage-related element. Such phages, phage satellites and phage-related elements are described herein. Also as described herein, in some preferred embodiments, the capsid is from a phage, examples of which are described herein.

[0204] By way of non-limiting example, as exemplified herein, a chimeric particle of the invention may comprise a tail from a second phage, phage satellite or phage-related element selected from the group consisting of HK022, HK106, EhCIEhh_18 JP25170, lambda or 80.

[0205] A person of ordinary skill in the art will readily be able to classify the genes within a first phage, phage satellite or phage-related element. Thus, said person of ordinary skill in the art will readily be able to classify the genes within a first phage, phage satellite or phage-related element which encode one or more tail protein.

[0206] The tail from a first phage, phage satellite or phage-related element is not particularly limited, provided that: (i) it is capable of delivering the encapsidated nucleic acid to a host cell; and (ii) assembling with a capsid as described herein to form a chimeric particle as described herein. For the avoidance of doubt, the particles of the invention are chimeric, and as such the capsid and tail are from different phages, phage satellites and phage-related elements. However, any given phage, phage satellite or phage-related element may be able to providethe capsid or the tail, provided that it does not provide both the capsid and the tail to an individual particle.

[0207] The tail comprised in a chimeric particle of the invention determines its host cell tropism. In other words, depending on the specific tail used, a chimeric particle may be capable of infecting different bacterial species and / or strains. By way of non-limiting example, two chimeric particles comprising the same capsid but with different tails may be capable of infecting different bacterial species, a range of overlapping (but not identical) bacterial species and / or strains, or different strains of the same bacterial species.

[0208] Non-limiting examples of tails which may be used in the present invention include the tail of E. coli phage HK022 permitting tropism towards E. coll (e.g. C1a, RHBSTW-00139, EDL933 JP 24888 and JP24699 as per Examples 3 and 4 below, as exemplified with the K. pneumoniae KpCIDSM30104 cf-PICI capsid). Other non-limiting examples of tails which may be used in the present invention include the tail of E. coli phage HK022 or HK106 permitting tropism towards E. coli C1a (see Example 4, exemplified with the E. coli EcCIGN02175 cf-PICI capsid) or the tail of E. coli phage HK106 permitting tropism towards E. coli C1a (see Example 4). Further non-limiting examples of tails which may be used in the present invention include the tail of any of the 5 prophages present in Enterobacter hormaechei Ehh_18 permitting tropism towards E. hormaechei JP25170 (see Example 7, as exemplified with the E. coli EcCIGN02175 cf-PICI capsid), the tail of any of the prophages present in Enterobacter hormaechei Ehh_18 permitting tropism towards E. hormaechei JP25149 (see Example 7, as exemplified with the E. coli EcCIGN02175 cf-PICI capsid), or the tail of the HK106 E. coli phage permitting tropism towards E. coli (see Example 7, as exemplified with the E. coli EcCIGN02175 cf-PICI capsid). Further non-limiting examples of tails which may be used in the present invention include the tail of E. coli phage lambda permitting tropism of the capsid of E. coli phage 80 towards E. coli cells expressing the LamB receptor or the tail of E. coli phage 80 permitting tropism of the capsid of E. coli phage lambda towards E. coli cells expressing the FhuA receptor.

[0209] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 20 to 26. A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 20 to 26.A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 20. A chimeric particle of the invention may comprise a tail which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 20.

[0210] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 21. A chimeric particle of the invention may comprise a tail which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 21.

[0211] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 22. A chimeric particle of the invention may comprise a tail which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 22.

[0212] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 23. A chimeric particle of the invention may comprise a tail which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 23.

[0213] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 24. A chimericparticle of the invention may comprise a tail which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 24.

[0214] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 25. A chimeric particle of the invention may comprise a tail which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 25.

[0215] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 26. A chimeric particle of the invention may comprise a tail which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 26.

[0216] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 20 to 26. In particular, a chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 20 to 26.

[0217] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of SEQ ID NO: 20.

[0218] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of SEQ ID NO: 21.

[0219] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of SEQ ID NO: 22.

[0220] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of SEQ ID NO: 23.A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of SEQ ID NO: 24.

[0221] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of SEQ ID NO: 25.

[0222] A chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of SEQ ID NO: 26.

[0223] A tail from a second phage, phage satellite or phage-related element may be capable of interacting with a capsid from a single first phage, phage satellite or phage-related element. Alternatively, a tail from a second phage, phage satellite or phage-related element may be capable of interacting with the capsid from two or more different first phages, phage satellites or phage-related elements.

[0224] Atail as defined herein may be isolated. An isolated tail is not associated with a capsid or other phage, phage satellite or phage related element components. By way of non-limiting example, a tail as produced in any of the methods provided by the invention may be isolated and / or purified to be formulated in separate combinations without the presence of a capsid or other phage, phage satellite or phage related element components. Any and all disclosure herein in relation to tails applies equally and without reservation to isolated tails unless expressly stated to the contrary. Thus, an isolated tail from the phage, phage satellite or phage-related element of the invention may be capable of assembling with a tail-less capsid of a phage, phage satellite or phage-related element capsid as defined herein. Said assembly may be via a neck comprised in the tail-less capsid. The neck may be any as described herein. By way of non-limiting example, the neck may comprise a portal protein, an adaptor protein and / or a connector protein, such as those described herein. An isolated tail may be capable of interacting with a tail-less capsid from a single different second infectious phage, phage satellites or phage-related elements. An isolated tail may be capable of interacting with a tailless capsid from two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) different second infectious phage, phage satellites or phage-related elements.

[0225] The invention also provides a composition comprising an isolated tail of the invention, or a population thereof.

[0226] The tail from a second phage, phage satellite or phage-related element may further comprise an amino acid sequence which is configured to connect to the capsid from the first phage, phage satellite or phage-related element. In particular, the tail may comprise an amino acid sequence which is configured to connect to the neck of the capsid from the first phage, phage satellite or phage-related element. Without being bound by theory, it is believed thatmodification of this amino acid sequence may modify the ability of the tail to connect to capsids from different first phages, phage satellites or phage-related elements.

[0227] Phages, phage satellites and phage-related elements often further comprise a tail tape measure protein (TMP), which dictates the tail length and facilitates DNA transit to the cell cytoplasm during infection. Exemplary TMP amino acid sequences are described herein.

[0228] A chimeric particle of the invention may further comprise a TMP which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 27 to 33. A chimeric particle of the invention may further comprise a TMP which has an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 27 to 33.

[0229] A chimeric particle of the invention may further comprise a TMP which has an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 27 to 33. In particular, a chimeric particle of the invention may further comprise a TMP which has an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 27 to 33.

[0230] Neck

[0231] A capsid from a first phage, phage satellite or phage-related element typically comprises a neck.

[0232] The term “neck” (also referred to interchangeably in the art as a “collar”) is a standard term of art which would be understood by one of ordinary skill to refer to a structural element which connects the capsid of a phage, phage satellite or phage-related element to a tail. The neck acts as a transition zone, facilitating the transfer of genetic material from the capsid to the tail during infection. The structure of the neck can differ between different phage. By way of non-limiting example, the neck of T4 phage comprises adaptor proteins gp3, gp15, gp13, gp14 and gp wac (fibritin). By way of further non-limiting example, the phage phi29 comprises a toroidal neck or collar, which is surrounded by 12 appendages. Irrespective of such differences, a person of ordinary skill in the art would be able to identify the neck of a given phage, phage satellite or phage-related element using routine sequence and structural techniques without undue burden.

[0233] The neck comprised in a chimeric particle of the invention is not particularly limited, provided it is capable of connecting the capsid from a first phage, phage satellite or phage-related element with the tail from a second phage, phage satellite or phage-related element. Thus, the neck is configured to connect the capsid from the first phage, phage satellite or phage-related element with the tail from the second phage, phage satellite or phage-relatedelement. In particular, the neck may comprise an amino acid sequence which is configured to connect to the tail from the second phage, phage satellite or phage-related element. Without being bound by theory, it is believed that modification of the neck or an amino acid sequence comprised in the neck may modify the ability of the capsid to connect to tails from different second phages, phage satellites or phage-related elements.

[0234] The necks of cf-PICIs are of particular interest in the context of chimeric particles of the invention. As described herein, the genomes of cf-PICIs do not encode tails, and whilst cf-PICIs can produce tail-less capsids, they rely on parasitising the tails of other phages, phage satellites and phage-related elements to produce infectious particles. Without being bound by theory, it is believed that the necks of cf-PICIs may be particularly suited to use in chimeric particles of the invention, because the need to parasitise the tails of other phages, phage satellites and phage-related elements means that the cf-PICI necks may be more amenable to connecting with tails from a number of different tails phages, phage satellites and phage-related elements. As exemplified herein, the neck from KpCIDSM30104 is capable of connecting the KpCIDSM30104 capsid with the tail from HK022. Also as exemplified herein, the neck from EcCIGN02175 is capable of connecting the EcCIGN02175 capsid with the tails from HK022, HK106 and prophages present in E. hormaechei Ehh_18. Also as exemplified herein, the neck from EcCIEDL933 is capable of connecting the EcCIEDL933 capsid with the tail from HK106. Also as exemplified herein, the neck from lambda phage is capable of connecting the capsid from lambda phage to the tail of 80 phage. Also as exemplified herein, the neck from 80 phage is capable of connecting the capsid from 80 phage with the tail from lambda phage. Further, the neck from EcCIEDL933 (as exemplified by the connector and adaptor proteins thereof) is capable of connecting the KpCIDSM30104 capsid with the tail from HK106. Further, the neck from EcCIGN02175 (as exemplified by the connector and adaptor proteins thereof) is capable of connecting the KpCIDSM30104 capsid with the tail from HK022 and HK106.

[0235] A chimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 18 or 19. A chimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 18 or 19.

[0236] A chimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 18. Achimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 18.

[0237] A chimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 19. Achimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 19.

[0238] A chimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 18 or 19.

[0239] A chimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 18.

[0240] A chimeric particle of the invention may comprise a neck protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 19.

[0241] The neck of a first phage, phage satellite or phage-related element may comprise or consist of a single protein. Alternatively, the neck of a first phage, phage satellite or phage-related element may comprise or consist of two or more proteins, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more proteins. When the neck of a first phage, phage satellite or phage-related element may comprise or consist of two or more proteins, each of the two or more proteins may be a different protein, or there may be repeats of any one or more of said proteins.

[0242] In some embodiments, the neck of a first phage, phage satellite or phage-related element may comprise or consist of an adaptor protein (also referred to interchangeably herein as a capsid-tail adaptor protein) and a connector protein (also referred to interchangeably herein as a capsid-tail connector protein).

[0243] The adaptor protein and connector protein may be selected independently and are not particularly limited, provided that they are capable of forming a chimeric particle with a capsid and tail as described herein. A capsid from a first phage, phage satellite or phage-related element may comprise an adaptor protein and / or a connector protein from the same phage, phage satellite or phage-related element. Alternatively, a capsid from a first phage, phage satellite or phage-related element may comprise an adaptor protein and a connector, one of which is from the same phage, phage satellite or phage-related element as the capsid, and the other of which is from a different phage, phage satellite or phage-related element as thecapsid. Further alternatively, a capsid from a first phage, phage satellite or phage-related element may comprise an adaptor protein and / or a connector protein from a different phage, phage satellite or phage-related element. The adaptor protein and connector protein may be from the same phage, phage satellite or phage-related element (which is a different phage, phage satellite or phage-related element from which the capsid is derived), or may each independently be from a different phage, phage satellite or phage-related element (each of which is a different phage, phage satellite or phage-related element from which the capsid is derived). The phage, phage satellite or phage-related element from which the capsid and / or the neck (adaptor protein and / or connector protein) are derived may be different from the second phage, phage satellite or phage-related element from which the tail is derived.

[0244] In particular, wherein the first phage, phage satellite or phage-related element is a cf-PICI, the neck of said cf-PICI may comprise or consist of an adaptor protein and a connector protein. The adaptor protein and a connector protein which form part of a cf-PICI capsid may be selected independently and are not particularly limited, provided that they are capable of forming a chimeric particle with a cf-PICI capsid and tail as described herein. A capsid from a first cf-PICI strain may comprise an adaptor protein and / or a connector protein from the same cf-PICI strain. Alternatively, a capsid from a first cf-PICI strain may comprise an adaptor protein and a connector, one of which is from the same cf-PICI strain as the capsid, and the other of which is from a different cf-PICI strain to the capsid. Further alternatively, a capsid from a first cf-PICI strain may comprise an adaptor protein and / or a connector protein from a different cf-PICI strain. The adaptor protein and connector protein may be from the same cf-PICI strain (which is different cf-PICI strain to the cf-PICI strain from which the capsid is derived), or may each independently be from a different cf-PICI strain (each of which is a different cf-PICI strain to the cf-PICI strain from which the capsid is derived). The cf-PICI strain from which the capsid and / or the neck (adaptor protein and / or connector protein) are derived may be different from the second phage, phage satellite or phage-related element from which the tail is derived. By way of non-limiting example, the necks from the cf-PICIs KpCIDSM30104, EcCIGN02175 or EcCIEDL933 each comprise an adaptor protein and a connector protein, as illustrated for KpCIDSM30104 and EcCIGN02175 in Figure 1A.

[0245] In some embodiments, the neck of a first phage, phage satellite or phage-related element may comprise or consist of a portal protein (also referred to interchangeably herein as a capsid portal protein), an adaptor protein (also referred to interchangeably herein as a capsid-tail adaptor protein) and a connector protein (also referred to interchangeably herein as a capsid-tail connector protein).

[0246] The portal protein, adaptor protein and connector protein may be selected independently and are not particularly limited, provided that they are capable of forming a chimeric particle with a capsid and tail as described herein. The portal protein, adaptor proteinand / or connector protein may all be from the same phage, phage satellite or phage-related element. Alternatively, the portal protein and adaptor protein may be from the same phage, phage satellite or phage-related element and the connector protein may be from a different phage, phage satellite or phage-related element. Alternatively, the portal protein and connector protein may be from the same phage, phage satellite or phage-related element and the adaptor protein may be from a different phage, phage satellite or phage-related element. Alternatively, the adaptor protein and connector protein may be from the same phage, phage satellite or phage-related element and the portal protein may be from a different phage, phage satellite or phage-related element. Alternatively, the portal protein, adaptor protein and / or connector protein may all be from different phage, phage satellites or phage-related elements. In each case, the portal protein, adaptor protein and / or connector protein may be from the same phage, phage satellite or phage-related element as the capsid, or from a different phage, phage satellite or phage-related element as the capsid. For example, a capsid from a first phage, phage satellite or phage-related element may comprise a portal protein, an adaptor protein and connector protein from the same phage, phage satellite or phage-related element (which is a different phage, phage satellite or phage-related element from which the capsid is derived), or may each independently be from a different phage, phage satellite or phage-related element (each of which is a different phage, phage satellite or phage-related element from which the capsid is derived). The phage, phage satellite or phage-related element from which the capsid and / or the neck (portal protein, adaptor protein and / or connector protein) are derived may be different from the second phage, phage satellite or phage-related element from which the tail is derived.

[0247] In particular, wherein the first phage, phage satellite or phage-related element is a cf-PICI, the neck of said cf-PICI may comprise or consist of a portal protein, an adaptor protein and a connector protein. By way of non-limiting example, the necks from the cf-PICIs KpCIDSM30104, EcCIGN02175 or EcCIEDL933 each comprise a portal protein, an adaptor protein and a connector protein, as illustrated for KpCIDSM30104 and EcCIGN02175 in Figure 1A.

[0248] The portal protein, adaptor protein and connector protein may be selected independently and are not particularly limited, provided that they are capable of forming a chimeric particle with a capsid and tail as described herein. The portal protein, adaptor protein and / or connector protein may all be from the same cf-PICI strain. Alternatively, the portal protein and adaptor protein may be from the same cf-PICI strain and the connector protein may be from a different cf-PICI strain. Alternatively, the portal protein and connector protein may be from the same cf-PICI strain and the adaptor protein may be from a cf-PICI strain. Alternatively, the adaptor protein and connector protein may be from the same cf-PICI strain and the portal protein may be from a different cf-PICI strain. Alternatively, the portal protein,adaptor protein and / or connector protein may all be from different cf-PICI strain. In each case, the portal protein, adaptor protein and / or connector protein may be from the same cf-PICI strain as the capsid, or from a cf-PICI strain as the capsid. For example, a capsid from a first cf-PICI strain may comprise a portal protein, an adaptor protein and connector protein from the same cf-PICI strain (which is different to the phage, phage satellite or phage-related element from which the capsid is derived), or may each independently be from a different cf-PICI strain (each of which is different to the phage, phage satellite or phage-related element from which the capsid is derived). A capsid from a first cf-PICI strain may comprise a portal protein, an adaptor protein and a connector protein from the same cf-PICI strain. The cf-PICI strain from which the capsid and / or the neck (portal protein, an adaptor protein and / or a connector protein) are derived may be different from the second phage, phage satellite or phage-related element from which the tail is derived. By way of non-limiting example, a capsid from EcCIGN02175 may further comprise a portal protein, an adaptor protein and a connector protein from KpCIDSM30104 as described in Example 13. This specific property of neck component exchange has been demonstrated for the first time in cf-PICIs, as exemplified herein. Thus, in some embodiments, the capsid from a phage, phage satellite or phage-related element comprises a neck (e.g. portal protein, adaptor protein and / or connector protein) from the same class of phage, phage satellite or phage-related element. In some embodiments, the capsid from a phage, phage satellite or phage-related element comprises a neck (e.g. portal protein, adaptor protein and / or connector protein) from the same phage, phage satellite or phage-related element.

[0249] A chimeric particle of the invention may comprise a neck from KpCIDSM30104, EcCIGN02175 and / or EcCIEDL933. In particular, a chimeric particle of the invention may comprise an adaptor protein and / or a connector protein from KpCIDSM30104, EcCIGN02175 and / or EcCIEDL933, typically wherein said particles comprise both an adaptor protein and a connector protein from KpCIDSM30104, EcCIGN02175 and / or EcCIEDL933, and preferably wherein the adaptor protein and connector protein are both from KpCIDSM30104, EcCIGN02175 or EcCIEDL933.

[0250] A chimeric particle of the invention may comprise a neck from KpCIDSM30104, EcCIGN02175 and / or EcCIEDL933. In particular, a chimeric particle of the invention may comprise a portal protein, an adaptor protein and / or a connector protein from KpCIDSM30104, EcCIGN02175 and / or EcCIEDL933, typically wherein said particles comprise a portal protein, an adaptor protein and a connector protein from KpCIDSM30104, EcCIGN02175 and / or EcCIEDL933, and preferably wherein the adaptor protein and connector protein are all from KpCIDSM30104, EcCIGN02175 or EcCIEDL933.

[0251] A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity(e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 35 to 37. A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 35 to 37.

[0252] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 8 to 12. A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 8 to 12.

[0253] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 8 to 10. A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 8 to 10.

[0254] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 8. A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 8.

[0255] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 9. A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acidsequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 9.

[0256] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 10. A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 10.

[0257] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 11. A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 11.

[0258] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 12. A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 12.

[0259] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 8 to 12.

[0260] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 8 to 10.

[0261] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 8.

[0262] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 9.A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 10.

[0263] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 11.

[0264] A chimeric particle of the invention may comprise an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 12.

[0265] Alternatively or in addition, a chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 13to 17. A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 13to 17.

[0266] In particular, alternatively or in addition to an adaptor protein as described herein, a chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 13 to 15. A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 13 to 15.

[0267] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 13. A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 13.

[0268] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 14. A chimeric particle of theinvention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 14.

[0269] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 15. A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 15.

[0270] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 16. A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 16.

[0271] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 17. A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 17.

[0272] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 13 to 17.

[0273] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 13 to 15.

[0274] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 13.

[0275] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 14.A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 15.

[0276] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 16.

[0277] A chimeric particle of the invention may comprise a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 17.

[0278] Further alternatively or in addition, a chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 35. A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 35.

[0279] A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 36. A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 36.

[0280] A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 37. A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 37.

[0281] A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 35 to 37.

[0282] A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 35.

[0283] A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 36.A chimeric particle of the invention may comprise a portal protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 37.

[0284] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 8 to 12; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 13 to 17. A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 8 to 12; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs 13 to 17.

[0285] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 8 to 10; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 13 to 15. A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 8 to 10; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 13 to 15.

[0286] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%,at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 8; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 13. A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 8; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 13.

[0287] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 9; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 14. A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 9; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 14.

[0288] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 10; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 15. A chimeric particle of the invention may comprise: (i) an adaptor protein whichcomprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 10; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 15.

[0289] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 11; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 16. A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 11; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 16.

[0290] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 12; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 17. A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 12; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 17.

[0291] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQID NOs: 8 to 12; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 13 to 17.

[0292] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 8 to 10; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 13 to 15.

[0293] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 8; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 13.

[0294] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 9; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 14.

[0295] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 10; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 15.

[0296] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 11; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 16.

[0297] A chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 12; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 17.

[0298] A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 35 to 37; (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 8 to 12; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%,at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 13 to 17. A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 35 to 37; (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs: 8 to 12; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to any one of SEQ ID NOs 13 to 17.

[0299] A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 35; (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 8; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 13. A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 35; (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 8; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 13.

[0300] A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 36; (ii) an adaptor protein whichcomprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 9; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 14. A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 36; (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 9; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 14.

[0301] A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 37; (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 10; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to SEQ ID NO: 15. A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 37; (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 10; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 80%, preferably at least 90%, more preferably at least 95% sequence identity to SEQ ID NO: 15.A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 35 to 37 (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 8 to 12; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 13 to 17.

[0302] A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 35 (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 8; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 13.

[0303] A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 36 (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 9; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 14.

[0304] A chimeric particle of the invention may comprise: (i) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 37 (ii) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 10; and (iii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of SEQ ID NO: 15.

[0305] Nucleic acids

[0306] Phages, phage satellites or phage-related elements comprise genomes which, in addition to the genes requires for their own genome replication and packaging, as well as genes encoding structural elements such as capsid proteins, neck proteins (e.g. adaptor and / or connector proteins) and tail proteins, if present. The genomes of phages, phage satellites or phage-related elements can also comprise a wide range of auxiliary or accessory genes, including those encoding a wide range of virulence and resistance factors, genes involved in host adaptation, and antimicrobial resistance determinants that can ultimately transform a non-pathogenic bacterial strain into a pathogenic one.

[0307] A chimeric particle of the invention may comprise a nucleic acid molecule (also referred to interchangeably herein as a genome). Said nucleic acid molecule may be DNA or RNA; preferably said nucleic acid molecule may be DNA.

[0308] The genome is not particularly limited, provided that it is capable of encapsidation by a capsid of the invention. Thus, the genome may be of between about 7.5 kb to about 160 kb, such as between about 7.5 kb to about 25 kb in size, between about 7.5 kb to about 22.5 kb,between about 7.5 kb to about 20 kb, between about 7.5 kb to about 19 kb, between about 7.5 kb to about 18 kb, between about 7.5 kb to about 17.5 kb, between about 7.5 kb to about 15 kb, between about 10 kb to about 22.5 kb, between about 10 kb to about 20 kb, between about 10 kb to about 19 kb, between about 10 kb to about 18 kb, between about 10 kb to about 17.5 kb, between about 10 kb to about 15 kb.

[0309] The genome typically comprises or consists of a nucleic acid sequence that is exogenous to the genome of the first phage, phage satellite or phage-related element and / or the genome of the second phage, phage satellite or phage-related element. The genome of a chimeric particle of the invention may comprise or consist of a nucleic acid sequence that is exogenous to the genome of both the first phage, phage satellite or phage-related element and the genome of the second phage, phage satellite or phage-related element.

[0310] The genome may be an exogenous nucleic acid molecule compared with the genome of the first phage, phage satellite or phage-related element and / or the genome of the second phage, phage satellite or phage-related element, preferably wherein the nucleic acid molecule is an exogenous nucleic acid molecule compared with the nucleic acid molecules of both the first and second phage, phage satellite or phage-related element.

[0311] The genome of a chimeric particle is not particularly limited, but typically comprises or consists of one or more exogenous gene (or genetic element). Said exogenous gene (or genetic element) typically confers a functional property on the chimeric particle, rendering is useful in one or more application such as those described herein. By way of non-limiting example, the genome may comprise or consist of one or more gene (or genetic element) selected from the group consisting of: (a) a gene (or genetic element) which encodes protein capable of killing one or more target bacteria, optionally (i) a gene (or genetic element) which encodes an antibiotic and / or a protein which reduces antibiotic resistance; and / or (ii) a gene (or genetic element) which encodes a lytic enzyme; (b) a gene (or genetic element) which encodes a reporter protein, e.g. a fluorescent protein or an enzymatic marker; (c) a gene (or genetic element) which encodes a protein which alters the physiology of the target bacteria; and / or (d) a gene (or genetic element) which modifies the genome of one or more target bacteria, or which encodes a protein which modifies the genome of one or more target bacteria.

[0312] Non-limiting examples of suitable exogenous genes include any one or any combination of a biofilm decomposition gene, an antigen presentation gene, a transfer gene, and a bactericidal gene.

[0313] Non-limiting examples of biofilm decomposition genes include dextranases, proteases, etc. that cut or degrade the molecular structure of biofilms consisting of bacterial polysaccharides, peptidoglycans, proteins, etc.Non-limiting examples of antigen-presenting genes include any gene that makes the antigen easily recognised by the immune system or presents an antigen that is a target of attack. This antigen does not necessarily have to be an antigen against the bacteria that is infected by the chimeric particle, but may be an antigen against other pathogenic organisms, viruses, animal tumours, etc. present in the lesion. Thus, the genome of a chimeric particle of the invention may comprise nucleic acid from a pathogenic bacteria, intestinal flora bacteria, or other bacteria, or present an antigen on the surface of the phage capsid. It can also be used in the field of phage vaccines. It will also be applicable to cancer treatment and treatment of genetic diseases.

[0314] Exogenous genes can also be used to add functions to bacteria infected by the chimeric particle. For example, it is possible to add genes related to the synthesis, secretion, etc. of proteins and various substances to add this function.

[0315] A plurality of exogenous genes (e.g. 2, 3, 4, 5, 6, 78, or more exogenous genes) can be included in the genome of a chimeric particle of the invention. By way of non-limiting example, a plurality of exogenous genes can comprise a gene encoding for a drug, a gene encoding for a protein which reduces resistance to said drug, a gene encoding a protein associated with attenuation or potentiation of an activity, a toxin gene, a specific metabolite gene, an enzyme gene for producing a specific metabolite.

[0316] Other non-limiting examples of exogenous genes include genes for identifying a bacterium, a reporter gene used for transformation, a sequence containing restriction enzymes or sticky ends used for genetic recombination, a repeat sequence, or other "genes" indicating genetic type in a broad sense.

[0317] An exogenous genes may cause a loss of drug resistance or cause drug resistance through nucleic acid acquisition and / or nucleic acid mutation. Specifically, resistant bacteria may arise from the acquisition of foreign DNA or RNA (nucleic acid) and / or nucleic acid mutation, so exogenous genes that suppress this nucleic acid acquisition and / or nucleic acid mutation may reduce the antibacterial effect. Such bactericidal genes may produce a secreted bactericidal product. Specifically, the bactericidal gene according to this embodiment makes it possible to produce a secreted bactericidal product that sterilises surrounding bacteria. That is, by loading the B-CAP according to this embodiment with a sterilising gene that produces a secreted sterilising product, it is possible to sterilise the target bacterium and the bacterial group around the target bacterium (collective sterilisation). For example, chimeric particles can be loaded with secretory bactericidal DNA machinery as an exogenous gene.

[0318] Wherein the genome of a chimeric particle comprises a plurality of exogenous genes, these may be arranged consecutively or as a plurality of sites within the sequence, or may be configured to include a plurality of them. For example, by loading multiple bactericidal genes so that it can be applied to multiple types of bacteria, one chimeric particle can be applied tomultiple resistant bacteria. Furthermore, in the case of multidrug-resistant bacteria that have multiple resistance genes, it is also possible to improve antibacterial efficiency by installing multiple genes that correspond to all of these genes. Furthermore, it is possible to further enhance the antibacterial effect by loading chimeric particles with any combination of the above-mentioned bactericidal genes, biofilm degrading genes, antigen presenting genes, and transducing genes.

[0319] The exogenous gene can be any gene or combination thereof. Furthermore, the exogenous gene(s) may include a gene that is expressed concomitantly with, whose expression is regulated, or associated with a drug resistance gene or a toxin gene. In addition, the foreign gene may include other pathogenic genes related to pathogenicity and genes that suppress these genes.

[0320] Furthermore, the exogenous gene of this embodiment may be a "gene" in a broad sense, such as a gene mutation sequence, a single base substitution, or a repeat, which is a target for cancer treatment or a genetic disease. In this case, it is also possible to administer bacteria comprising the chimeric particles for treatment as drug carriers. That is, it can also be applied to applications where a drug compatible with cells containing this exogenous gene is contained in the cytoplasm of a target bacterium, and then disseminated into tissues or around the target cells by lysis. In this case, it is also possible to provide the bacteria themselves containing the chimeric particles. It may also include chimeric particles that are activated by a specific immune response.

[0321] By way of further example, chimeric particles of the invention may be used as a therapeutic composition for treating an infectious disease. However, this treatment can be used not only for infectious disease treatment itself, but also for modifying bacterial flora, pretreatment for faecal transplants, etc. Specifically, it is also possible to use an antigen-presenting gene as an exogenous gene to induce immunity against bacteria necessary for treatment within the bacterial flora. By way of a further non-limiting example, chimeric particles of the invention may be carrying nucleic acid encoding for CRISPR-Cas systems, bactericidal enzymes such as lysin, antisense oligonucleotides the expression of which alters the function of essential genes of the infected bacterial cells, or reporter genes for detection of the infected bacterial cell.

[0322] The genome of a chimeric particle may additionally comprise or consist of genes encoding elements of the first phage, phage satellite or phage-related element. Thus, the genome of a chimeric particle may comprise genes encoding packaging elements, such as the capsid, neck (e.g. adaptor protein and / or connector protein), as well as elements required for the replication of the chimeric particle, such as those described herein.Tail-less capsids

[0323] Interestingly, the present inventors are the first report that the recently-discovered class of phage satellites, cf-PICIs produce stable, mature tail-less capsid which contain DNA, and that these tail-less capsids are capable of release into the environment. These new and surprising elements were found to not be infective but showed an ability to assemble in modular fashion with several phage tails originating from different host bacterial species and strains.

[0324] Whilst cf-PICIs have been described in the art, the present inventors are the first to appreciate that these tail-less, DNA-containing capsids have the potential to allow chimeric particles to be designed and produced with the tail targeted to mediate delivery of the encapsidated DNA to target cells of interest. The present invention therefore opens up an entirely new paradigm for the development of phage-based products, for therapy and for other applications where phages are already in use.

[0325] The invention therefore provides a tail-less capsid from a phage, phage satellite or phage-related element, which comprises a nucleic acid molecule.

[0326] The tail-less capsid may be from a phage, phage satellite or phage-related element as defined herein. By way of non-limiting example, the tail-less capsid may be from a cf-PICI.

[0327] The tail-less capsid may further comprise a neck which is configured to connect the capsid from the first phage, phage satellite or phage-related element with the tail from the second phage, phage satellite or phage-related element. The neck may be as described herein. By way of non-limiting example, the neck may comprise an adaptor protein and / or a connector protein, such as those described herein. By way of a further non-limiting example, the neck may comprise a portal protein, an adaptor protein and / or a connector protein, such as those described herein.

[0328] Atail-less capsid may be capable of interacting with a tail from a single second phage, phage satellite or phage-related element. Alternatively, a tail-less capsid may be capable of interacting with a tail from two or more different second infectious phage, phage satellites or phage-related elements.

[0329] The nucleic acid molecule encapsidated by a tail-less capsid protein of the invention may be any nucleic acid molecule as described herein. By way of non-limiting example, said nucleic acid molecule may comprise one or more exogenous gene, such as those described herein.

[0330] Atail-less capsid of the invention may be isolated. By way of non-limiting example, a tail-less capsid as produced in any of the methods provided by the invention may be isolated and / or purified to be formulated in separate combinations without the presence of a tail or other phage, phage satellite or phage related element components.A tail-less capsid of the invention may be non-enveloped. Typically, tail-less capsid of the invention are produced in and released from bacterium by canonical SOS induction and lysis, therefore resulting in non-enveloped tail-less capsids. “Non-enveloped” in the context of tail-less capsids refers to tail-less capsids which are not lipid-enveloped.

[0331] The invention also provides a composition comprising a tail-less capsid of the invention, or a population thereof.

[0332] The invention also provides a method of producing a tail-less capsid of the invention, said method comprising: (a) culturing a bacterial cell comprising a nucleic acid or expression vector encoding the tail-less capsid under conditions for production of a tail-less capsid. Optionally said method further comprises purifying the resulting tail-less capsid. Further optionally said method comprises introducing the nucleic acid or expression vector into the bacterial cell.

[0333] Isolated tails

[0334] As exemplified herein, the inventors have demonstrated for the first time that tails from phages, phage satellites and phage-related elements, particularly tails from cf-PICI, are capable of binding to bacterial cells even when the tail is not associated with a capsid (i.e. in the form of a complete particle). Without being bound by theory, once bound to a bacterial cell, the tails can then act as receptors for tail-less capsids. This mechanism has the potential to allow tails to be administered independently of capsids, and in particular for tails to be prepared as a stock reagent to allow different capsids to be targeted to a given bacterial cell of interest. This could potentially simplify manufacturing and supply chains, as streamlining the number of tails required, and allowing a modular approach where different capsids (and cargos) are produced according to demand / target of interest and used with a common / core panel of tails.

[0335] Accordingly, the present invention provides isolated tails and panels thereof, as described herein. An isolated tail is one which is not associated with a capsid to form an infectious particle. Unless expressly stated to the contrary, all disclosure in relation to tails herein applies equally and without reservation to isolated tails (and panels thereof) unless expressly stated to the contrary.

[0336] By way of non-limiting example, the invention provides an isolated tail, wherein: (a) the phage, phage satellite or phage-related element any is as defined herein, preferably a cf-PICI; (b) the isolated tail from a second phage, phage satellite or phage-related element is capable of assembling with the tail-less capsid of a first phage, phage satellite or phage-related element capsid via a neck comprised in the tail-less capsid, wherein optionally said neck is as defined herein, optionally a neck from a cf-PICI; and / or (c) the isolated tail is capable of interacting with (i) a tail-less capsid from a single first phage, phage satellite or phage-relatedelement or (ii) a tail-less capsid from two or more different first phage, phage satellites or phage-related elements.

[0337] The invention also provides a method of producing an isolated tail of the invention, said method comprising: (a) culturing a bacterial cell comprising a nucleic acid or expression vector encoding the isolated tail under conditions for production of an isolated tail. Optionally said method further comprises purifying the resulting isolated tail. Further optionally said method comprises introducing the nucleic acid or expression vector encoding the isolated tail into the bacterial cell.

[0338] Chimeric particles

[0339] Phages, phage satellites and phage-related elements as described herein utilise the same mechanisms and strategies for genome (e.g. DNA) packaging. These mechanisms and strategies are highly conserved between different phages, phage satellites and phage-related elements. In particular, it is well-known in the art that DNA packaging of phage or satellite DNAs into large or small capsids, respectively, and phage tail formation, are two processes that occur simultaneously but independently in the bacterial cells (Deeb (1970). J. Virol. 5, 27–31). Other common mechanisms can include those involved in capsid maturation, tail assembly and the formation of the infective particles. Once the DNAs are packaged and the capsids matured, the formed tails attach to them, creating the infective phage or satellite particles. It is also well-known that the host range of a phage is primarily determined by phage tail fibers (or spikes), which initially mediate reversible and specific recognition and adsorption by susceptible bacteria. (Nobrega et al. (2018). Nat. Rev. Microbiol. 16, 760-773). For instance, as exemplified herein, different cf-PICIs are each capable of forming chimeric particles using tails from phages, and capsids from individual cf-PICIs are capable of forming chimeric particles with different phage tails. In addition, it is shown herein that the capsids from two different phages, lambda and 80 are each capable of forming chimeric particles with tails from a different phage. Based on the general consensus that genome (e.g. DNA) packaging by phages, phage satellites and phage-related elements occurs via shared mechanisms, and the proof of concept data for exemplary chimeric particles provided in the Examples herein, one of ordinary skill in the art will appreciate that that capsids for phages, phage satellites and phage-related elements are capable of binding to a range of tails from other phages, phage satellites and phage-related elements to form chimeric particles according to the invention. In particular, as exemplified herein, the capsids of cf-PICIs have been demonstrated to be capable of exchanging components of the neck (e.g. portal protein, adaptor protein and / or connector protein) to facilitate formation of chimeric infectious particles with tails from other phages, phage satellites and phage-related elements.Accordingly, the invention provides chimeric particles which comprise a capsid from a first phage, phage satellite or phage-related element and a tail from a second phage, phage satellite or phage-related element. The first phage, phage satellite or phage-related element and the second phage, phage satellite or phage-related element are different.

[0340] As used herein, in relation to the first and second phage, phage satellite or phage-related elements, the term “different” may also be used interchangeably as phage, phage satellite or phage-related elements that are not originating from the same host bacterial strain and / or species, or that they are not found in nature to be present in the same host bacterial strain and / or species. In other words, the first and second phage, phage satellite or phage-related element are not endogenous to the same host bacterial species, strain and / or cell (i.e. as referred to in the examples, the second phage, phage satellite or phage-related element may not be a resident helper second phage, phage satellite or phage-related element for the first phage, phage satellite or phage-related element). The first and second phage, phage satellite or phage-related elements may not be endogenous to the same host bacterial species. The first and second phage, phage satellite or phage-related elements may not be endogenous to the same host bacterial strain. The first and second phage, phage satellite or phage-related elements may not be endogenous to the same host bacterial cell. Thus, the capsid from a first phage, phage satellite or phage-related element and the tail from a second phage, phage satellite or phage-related element may not be found together in the cells of naturally occurring host bacterial strains and / or species.

[0341] By way of a non-limiting example to illustrate chimeric particles that may be excluded from chimeric particles according to the invention, a chimeric infectious particle may not comprise the capsid from a first E. coli phage, phage satellite or phage-related element and the tail from a second E. coli phage, phage satellite or phage-related element are not contemplated in the present invention (i.e. the first and second phage, phage satellite or phage-related element do not originate from the same host bacterial species).

[0342] By way of a further illustrative example, a chimeric infectious particle may not comprise the capsid from a first E. coli phage, phage satellite or phage-related element and the tail from a second E. coli phage, phage satellite or phage-related element wherein the first E. coll phage, phage satellite or phage-related element and the second E. coll phage, phage satellite or phage-related element are not endogenous to the same strain of E. coll (i.e. the first and second phage, phage satellite or phage-related element do not originate from the same strain of a given bacterial species).

[0343] In particular, a chimeric particle of the invention may not comprise the capsid of an E.coli cf-PICI (EcCIEDL933, e.g. SEQ ID NO: 3) combined with the tail of the E. coll helper phage HK106 (e.g. SEQ ID NO: 21), such as the infectious particle described in Alqurainy et al (2023). Cell Host Microbe 31, 69-82.e5.By way of a non-limiting example to illustrate chimeric particles that may be encompassed by the invention, chimeric infectious particles combining the capsid from a K. pneuminiae phage, phage satellite or phage-related element and the tail from an E. coli phage, phage satellite or phage-related element, as exemplified in the present application, are contemplated. The skilled person in the art would readily understand that the nucleic acid sequences encoding the capsid from a K. pneuminiae phage, phage satellite or phage-related element and the tail from an E. coli phage, phage satellite or phage-related element would not be naturally present in the same host bacterial strain and / or species.

[0344] By way of a further non-limiting example to illustrate chimeric particles that may be encompassed by the invention, chimeric infectious particles combining the capsid from a first K. pneuminiae phage, phage satellite or phage-related element and the tail from a second K. pneuminiae phage, phage satellite or phage-related element are contemplated, provided that the first and second phage, phage satellite or phage-related element are not naturally present in the same strain of K. pneuminiae.

[0345] The first phage, phage satellite or phage-related element and the second phage, phage satellite or phage-related element may each be independently selected from phages, phage satellites and phage-related elements as described herein.

[0346] Thus, the first phage, phage satellite or phage-related element may be selected from any phage, phage satellite or phage-related element. The second phage, phage satellite or phage-related element may be selected from any phage, phage satellite or phage-related element, provided that the second phage, phage satellite or phage-related element is different from the first phage, phage satellite or phage-related element.

[0347] The first phage, phage satellite or phage-related element may be selected from a phage satellite. In particular, said first phage, phage satellite or phage-related element may be a phage satellite. Said phage satellite may be selected from a capsid-forming PICI (cf-PICI), a phage inducible chromosomal islands (PICI), a P4-like satellite, ora PICI-like element (PLE). Non-limiting examples of cf-PICIs, PICIs, P4-like satellites and PLEs are described herein. In some preferred embodiments, the first phage, phage satellite or phage-related element is a cf-PICI.

[0348] Accordingly, a chimeric particle of the invention may comprise a capsid from any first phage, phage satellite or phage-related element, and particularly may comprise a capsid from a phage satellite. In particular, a chimeric particle of the invention may comprise a capsid from a phage satellite selected from a capsid-forming PICI (cf-PICI), a phage inducible chromosomal islands (PICI), a P4-like satellite, or a PICI-like element (PLE). Non-limiting examples of cf-PICIs, PICIs, P4-like satellites and PLEs are described herein. In some preferred embodiments, a chimeric particle of the invention may comprise a capsid from a cf-PICI. Exemplary capsid sequences, and variants thereof, are described herein. Byway of non-limiting example, a chimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 1 to 7, particularly any one of SEQ ID NOs: 1 to 3, as described herein. In particular, and as exemplified herein, a chimeric particle of the invention may comprise a capsid which comprises or consists of a plurality of mature capsid proteins, each mature capsid protein having an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 1 to 7, particularly any one of SEQ ID NOs: 1 to 3.

[0349] The second phage, phage satellite or phage-related element is not limited, provided that it comprises a tail. In particular, said second phage, phage satellite or phage-related element may be a phage. Non-limiting examples of phages are described herein.

[0350] Accordingly, a chimeric particle of the invention may comprise a tail from any second phage, phage satellite or phage-related element, and particularly may comprise a capsid from a phage. Non-limiting examples of phages are described herein. Exemplary tail sequences, and variants thereof, are described herein. By way of non-limiting example, a chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 20 to 26. In particular, and as exemplified herein, a chimeric particle of the invention may comprise a tail which comprises or consists of a major tail protein which has an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 20 to 26.

[0351] The capsid of a chimeric particle of the invention may further comprise or consist of a neck. Non-limiting examples of necks and components thereof, such as portal proteins, adaptor proteins and connector proteins, are described herein. The neck or component(s) thereof may be from any first phage, phage satellite or phage-related element as described herein. In particular, said first phage, phage satellite or phage-related element may be a phage satellite. Said phage satellite may be selected from a capsid-forming PICI (cf-PICI), a phage inducible chromosomal islands (PICI), a P4-like satellite, or a PICI-like element (PLE). Nonlimiting examples of cf-PICIs, PICIs, P4-like satellites and PLEs are described herein. In some preferred embodiments, the first phage, phage satellite or phage-related element is a cf-PICI.

[0352] Accordingly, a chimeric particle of the invention may comprise a neck or component(s) thereof (e.g. a portal protein, an adaptor protein and / or connector protein) from any first phage, phage satellite or phage-related element, and particularly may comprise a neck orcomponent(s) thereof (e.g. a portal protein, an adaptor protein and / or connector protein) from a phage satellite. In particular, a chimeric particle of the invention may comprise a neck or component(s) thereof (e.g. a portal protein, an adaptor protein and / or connector protein) from a phage satellite selected from a capsid-forming PICI (cf-PICI), a phage inducible chromosomal islands (PICI), a P4-like satellite, or a PICI-like element (PLE). Non-limiting examples of cf-PICIs, PICIs, P4-like satellites and PLEs are described herein. In some preferred embodiments, a chimeric particle of the invention may comprise a neck or component(s) thereof (e.g. a portal protein, an adaptor protein and / or connector protein) from a cf-PICI. Exemplary adaptor protein and connector protein sequences, and variants thereof, are described herein. By way of non-limiting example, a chimeric particle of the invention may comprise: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 8 to 12, particularly any one of SEQ ID NOs: 8 to 10; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity (e.g. at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity) to any one of SEQ ID NOs: 13 to 17, particularly any one of SEQ ID NOs: 13 to 15, as described herein. In particular, and as exemplified herein, a chimeric particle of the invention may comprise a: (i) an adaptor protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 8 to 12, particularly any one of SEQ ID NOs: 8 to 10; and (ii) a connector protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 13 to 17, particularly any one of SEQ ID NOs: 13 to 15.

[0353] Non limiting examples of chimeric particles of the invention include particles comprising:

[0354] - a capsid from KpCIDSM30104; the adaptor protein of KpCIDSM30104; the connector protein of KpCIDSM30104 and a tail from HK022;

[0355] - a capsid from EcCIGN02175; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from HK022;

[0356] - a capsid from EcCIGN02175; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from HK106;

[0357] - a capsid from EcCIGN02175; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from prophages in E. hormaechei Ehh_18;- a capsid from KpCIDSM30104; the adaptor protein of EcCIEDL933; the connector protein of EcCIEDL933 and a tail from HK106;

[0358] - a capsid from KpCIDSM30104; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from HK022;

[0359] - a capsid from KpCIDSM30104; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from HK106;

[0360] - a capsid from KpCIDSM30104; the portal protein of KpCIDSM30104; the adaptor protein of KpCIDSM30104; the connector protein of KpCIDSM30104 and a tail from HK022;

[0361] - a capsid from EcCIGN02175; the portal protein of EcCIGN02175; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from HK022;

[0362] - a capsid from EcCIGN02175; the portal protein of EcCIGN02175; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from HK106;

[0363] - a capsid from EcCIGN02175; the portal protein of EcCIGN02175; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from prophages in E. hormaechei Ehh_18;

[0364] - a capsid from KpCIDSM30104; the portal protein of EcCIEDL933; the adaptor protein of EcCIEDL933; the connector protein of EcCIEDL933 and a tail from HK106;

[0365] - a capsid from KpCIDSM30104; the portal protein of EcCIGN02175; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from HK022;

[0366] - a capsid from KpCIDSM30104; the portal protein of EcCIGN02175; the adaptor protein of EcCIGN02175; the connector protein of EcCIGN02175 and a tail from HK106;

[0367] - a capsid from lambda phage; the neck of lambda phage and a tail from phage 80;

[0368] or

[0369] - a capsid from phage 80; the neck of phage 80 and a tail from lambda phage.

[0370] In particular, and as exemplified herein, a chimeric particle of the invention may comprise:

[0371] - a capsid from KpCIDSM30104 (comprising the capsid protein of SEQ ID NO: 1);

[0372] the adaptor protein of KpCIDSM30104 (SEQ ID NO: 8); the connector protein of KpCIDSM30104 (SEQ ID NO: 13) and a major tail protein from HK022 (SEQ ID NO: 20).- a capsid from EcCIGN02175 (comprising the capsid protein of SEQ ID NO: 2); the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from HK022 (SEQ ID NO: 20).

[0373] - a capsid from EcCIGN02175 (comprising the capsid protein of SEQ ID NO: 2); the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from HK106 (SEQ ID NO: 21).

[0374] - a capsid from EcCIGN02175 (comprising the capsid protein of SEQ ID NO: 2); the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from prophages in E. hormaechei Ehh_18 (e.g. any one of SEQ ID NO: 23, 23 or 24).

[0375] - a capsid from KpCIDSM30104 (comprising the capsid protein of SEQ ID NO: 1);

[0376] the adaptor protein of EcCIEDL933 (SEQ ID NO: 10); the connector protein of EcCIEDL933 (SEQ ID NO: 15) and a major tail protein from HK106 (SEQ ID NO: 21).

[0377] - a capsid from KpCIDSM30104 (comprising the capsid protein of SEQ ID NO: 1);

[0378] the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from HK022 (SEQ ID NO: 20).

[0379] - a capsid from KpCIDSM30104 (comprising the capsid protein of SEQ ID NO: 1);

[0380] the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from HK106 (SEQ ID NO: 21).

[0381] - a capsid from KpCIDSM30104 (comprising the capsid protein of SEQ ID NO: 1);

[0382] the portal protein of KpCIDSM30104 (SEQ ID NO: 35); the adaptor protein of KpCIDSM30104 (SEQ ID NO: 8); the connector protein of KpCIDSM30104 (SEQ ID NO: 13) and a major tail protein from HK022 (SEQ ID NO: 20).

[0383] - a capsid from EcCIGN02175 (comprising the capsid protein of SEQ ID NO: 2); the portal protein of EcCIGN02175 (SEQ ID NO: 36); the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from HK022 (SEQ ID NO: 20).

[0384] - a capsid from EcCIGN02175 (comprising the capsid protein of SEQ ID NO: 2); the portal protein of EcCIGN02175 (SEQ ID NO: 36); the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from HK106 (SEQ ID NO: 21).- a capsid from EcCIGN02175 (comprising the capsid protein of SEQ ID NO: 2); the portal protein of EcCIGN02175 (SEQ ID NO: 36); the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from prophages in E. hormaechei Ehh_18 (e.g. any one of SEQ ID NO: 23, 23 or 24).

[0385] - a capsid from KpCIDSM30104 (comprising the capsid protein of SEQ ID NO: 1);

[0386] the portal protein of EcCIEDL933 (SEQ ID NO: 37); the adaptor protein of EcCIEDL933 (SEQ ID NO: 10); the connector protein of EcCIEDL933 (SEQ ID NO: 15) and a major tail protein from HK106 (SEQ ID NO: 21).

[0387] - a capsid from KpCIDSM30104 (comprising the capsid protein of SEQ ID NO: 1);

[0388] the portal protein of EcCIGN02175 (SEQ ID NO: 36); the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from HK022 (SEQ ID NO: 20).

[0389] - a capsid from KpCIDSM30104 (comprising the capsid protein of SEQ ID NO: 1);

[0390] the portal protein of EcCIGN02175 (SEQ ID NO: 36); the adaptor protein of EcCIGN02175 (SEQ ID NO: 9); the connector protein of EcCIGN02175 (SEQ ID NO: 14) and a major tail protein from HK106 (SEQ ID NO: 21).

[0391] - a capsid from lambda phage (SEQ ID NO: 6); the neck of lambda phage (SEQ ID NO: 18) and a major tail protein from phage 80 (SEQ ID NO: 26); or

[0392] - a capsid from phage 80 (SEQ ID NO: 7); the neck of phage 80 (SEQ ID NO: 19) and a major tail protein from lambda phage (SEQ ID NO: 25).

[0393] A chimeric particle of the invention may comprise a genome (nucleic acid) as described herein. In particular, a chimeric particle of the invention may comprise a genome comprising one or more exogenous gene, such as those described herein.

[0394] A chimeric particle of the invention is typically infectious. In other words, a chimeric particle of the invention is typically capable of delivering its genome to a host (bacterial) cell, and once inside the host (bacterial) cell, the genome carry out its desired effect(s), e.g. replicating the chimeric particle (in the case of replication competent chimeric particles), expression of a therapeutic and / or reporter protein, modifying the genome of the host (bacterial cell), or any other effect such as those described herein. As described herein, delivery of the genome to the host cell is typically mediated by the tail of the chimeric particle. Infectivity of a chimeric particle of the invention may be determined and / or quantified by any appropriate technique, examples of which are known in the art. By way of non-limiting example, infectivity of a chimeric particle may be determined and / or quantified by plaque assay, reporter protein assay wherein the reporter protein encoding nucleic acid being carried by the chimeric particle, or antibiotic resistance assay wherein an antibiotic resistanceencoding nucleic acid being carried by the chimeric particle. All references herein to chimeric particles of the invention refer to chimeric infectious particles of the invention, unless expressly stated to the contrary.

[0395] A chimeric particle of the invention may be replication competent or replication deficient. A replication competent chimeric particle is capable of replicating within a host (bacterial) cell to produce copies of itself. A replication deficient chimeric particle is not capable of replicating within a host (bacterial) cell to produce copies of itself. A replication competent or replication deficient chimeric particle of the invention may be selected as appropriate depending on the intended application of said particle, such as for any of the examples described herein. By way of non-limiting example, if the genome of the chimeric particle comprises an exogenous gene which modifies the genome of the host cell, then a replicationdeficient chimeric particle may be used, as the technical effect may arise from the incorporation of a single copy of said exogenous gene into the host cell genome. By way of further non-limiting example, if the genome of the chimeric particle comprises encodes for a therapeutic protein, then a replication-competent chimeric particle may be used, as the technical effect may arise from the production of the therapeutic protein, such that there may be an advantage to a host cell containing multiple chimeric particles to increase expression of the therapeutic protein. Replication competence of a chimeric particle of the invention may be determined and / or quantified by any appropriate technique, examples of which are known in the art. By way of non-limiting example, replication competence of a chimeric particle may be determined and / or quantified by Southern blot or qPCR.

[0396] The capsid of a chimeric particle as described herein may be capable of interacting with the tail from a single second phage, phage satellite or phage-related element.

[0397] Alternatively, the capsid of a chimeric particle as described herein may be capable of interacting with the tail from two or more different second phages, phage satellites or phage-related elements. Thus, a population or panel of chimeric particles may be produced. If a plurality of capsids which are capable of interacting with the tail from two or more different second phages, phage satellites or phage-related elements are contacted with the tails from said two or more different second phages, phage satellites or phage-related elements, then the resulting population or panel of chimeric particles may comprises chimeric particles comprising the capsid interacting with the different second phages, phage satellites or phage-related elements, wherein each individual particle comprises a single tail type. By way of example, if a plurality of capsid “A” are contacted with a plurality of tail “X”, tail “Y” and tail “Z”, then the resulting population or panel may comprise chimeric particles “AX”, “AY” and “AZ”.

[0398] As described herein, the tail comprised in a chimeric particle of the invention determines its host cell tropism. In other words, depending on the specific tail used, a chimeric particle may be capable of infecting different bacterial species and / or strains. By way of non-limiting example, two chimeric particles comprising the same capsid but with different tails may be capable of infecting different bacterial species, a range of overlapping (but not identical) bacterial species and / or strains, or different strains of the same bacterial species.

[0399] Accordingly, a chimeric particle of the invention may be capable of infecting a single bacterial species or strain thereof, such as those described herein. Wherein a chimeric particle of the invention is capable of infecting a single bacterial species, it may be capable of infecting a single strain of said species, or two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) strains of said species. A chimeric particle of the invention may be capable of infecting two or more (e.g.

[0400] 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) different bacterial species. The two or more different bacterial species may be unrelated (e.g. in terms of sequence and / or phylogenetic classification) or related. Wherein a chimeric particle of the invention is capable of infecting two or more (e.g.

[0401] 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial species, it may be capable of infecting a single strain of each species, or two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) strains of any of said two or more bacterial species.

[0402] Non-limiting examples of chimeric particles include KpCIDSM30104 capsid with E. coli phage HK022 tail, EcCIGN02175 capsid with E. coli phage HK022 tail, EcCIGN02175 capsid with E. coli phage HK106 tail, EcCIGN02175 capsid with tail of prophages present in E. hormaechei Ehh_18, capsid of E. coli phage 80 with tail of E. coli phage lambda and capsid of E. coli phage lambda with tail of E. coli phage 80.

[0403] The invention also provides a population or plurality of a chimeric particle of the invention.

[0404] Panels

[0405] The invention also provides a panel comprising two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) chimeric particles as defined herein. The two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) chimeric particles may target the same bacterial species and / or strains thereof. The two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) chimeric particles may target different bacterial species and / or strains thereof. The two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) chimeric particles may target an overlapping range of bacterial species and / or strains thereof. In such instances, optionally each of the two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) chimeric particles targets at least one different bacterial species and / or strain.

[0406] The two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) chimeric particles within a panel may comprise the same capsid and different tails. By way of example, the capsids may be of type “A” and the tails may be of type “X” or “Y”, such that the panel may comprise chimeric particles “AX” and “AY”.

[0407] The two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) chimeric particles within a panel may comprise different capsids and the same tail. By way of example, the capsids may be oftype “A” and “B” and the tails may be of type “X”, such that the panel may comprise chimeric particles “AX” and “BX”.

[0408] The two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) chimeric particles within a panel may comprise different capsids and different tails. By way of example, the capsids may be of type “A” and “B” and the tails may be of type “X” or “Y”, such that the panel may comprise chimeric particles “AX”, “AY”, “BX” and “BY”.

[0409] As described herein, the tail comprised in a chimeric particle of the invention determines its host cell tropism. In other words, depending on the specific tail used, a chimeric particle may be capable of infecting different bacterial species and / or strains. Therefore, when a panel of chimeric particles comprises particles having tails from two or more different tails the chimeric particles within the panel may be capable of infecting different bacterial species, a range of overlapping (but not identical) bacterial species and / or strains, or different strains of the same bacterial species.

[0410] The invention also provides a panel of tail-less capsids as defined here. Unless expressly stated to the contrary, the disclosure herein in relation to panels of chimeric particles of the invention applies equally and without reservation to panels comprising tail-less capsids of the invention. By way of non-limiting example, the invention provides a panel of tail-less capsids which comprises two or more different tail-less capsids.

[0411] The invention also provides a panel of isolated tails as defined here. Unless expressly stated to the contrary, the disclosure herein in relation to panels of chimeric particles of the invention applies equally and without reservation to panels comprising isolated tails of the invention. By way of non-limiting example, the invention provides a panel of isolated tails which comprises two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) isolated tails as defined herein. The two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) isolated tails may target the same bacterial species and / or strains thereof. The two or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) isolated tails may target different bacterial species and / or strains thereof.

[0412] Compositions, formulations and kits

[0413] The invention also provides a composition comprising or consisting of: (a) a capsid from a first phage, phage satellite or phage-related element; and (b) a tail from a second phage, phage satellite or phage-related element. Typically, the first and second phage, phage satellite or phage-related element are different as described herein. Although said composition comprises or consists of both capsids and tails, these are typically not present as fully-assembled chimeric particles within the composition. In such instances, the capsid and the tail are typically capable of assembling to form a chimeric infectious particle according to the invention.A composition of the invention may comprise or consist of: (a) two or more different capsids; and / or (b) two or more different tails. Said capsids and tails may be independently selected, particularly from those described herein.

[0414] The invention also provides a composition comprising or consisting of an isolated tail from a second phage, phage satellite or phage-related element, optionally a cf-PICI, as described herein.

[0415] The invention also provides a composition comprising or consisting of a tail-less capsid from a first phage, phage satellite or phage-related element, optionally a cf-PICI, as described herein.

[0416] The invention also provides a pharmaceutical formulation comprising a chimeric particle or population thereof, a panel, or a composition of the invention, and at least one pharmaceutically acceptable carrier, excipient, buffer or diluent. The invention also provides a pharmaceutical formulation comprising a bacterial cell of the invention, and at least one pharmaceutically acceptable carrier, excipient, buffer or diluent.

[0417] The invention also provides a pharmaceutical formulation comprising or consisting of an isolated tail from a second phage, phage satellite or phage-related element, optionally a cf-PICI, as described herein, and at least one pharmaceutically acceptable carrier, excipient, buffer or diluent.

[0418] The invention also provides a pharmaceutical formulation comprising or consisting of tail-less capsid from a first phage, phage satellite or phage-related element, optionally a cf-PICI, as described herein, and at least one pharmaceutically acceptable carrier, excipient, buffer or diluent.

[0419] The pharmaceutical formulations, chimeric particles or populations thereof, isolated tails, tail-less capsids, panels and compositions of the invention may be administered or applied in any dosage appropriate for achieving the desired effect, which may be a therapeutic effect in the context of medical uses of the invention. Appropriate dosages may be determined by a practitioner, such as a clinician or other medical practitioner using standard techniques and within the normal course of their work.

[0420] Non-limiting examples of pharmaceutically acceptable carriers that may be comprised in a composition of the invention include water, saline, and phosphate-buffered saline. In some embodiments, however, the composition is in lyophilised form, in which case it may include a stabiliser, such as bovine serum albumin (BSA). In some embodiments, it may be desirable to formulate the composition with a preservative, such as thiomersal or sodium azide, to facilitate long-term storage.

[0421] The invention also provides a kit of parts comprising or consisting of: (a) a first composition comprising or consisting of a capsid from a first phage, phage satellite or phage-related element; and (b) a second composition comprising or consisting of a tail from a second phage, phage satellite or phage-related element.

[0422] The invention also provides a kit of parts comprising or consisting of: (a) a first composition comprising or consisting of a tail-less capsid from a first phage, phage satellite or phage-related element or a panel of tail-less capsids of the invention; and (b) a second composition comprising or consisting of an isolated tail from a second phage, phage satellite or phage-related element or a panel of isolated tails of the invention. Typically, the tail-less capsid from a first phage, phage satellite or phage-related element or a panel of tail-less capsids of the invention and the isolated tail from a second phage, phage satellite or phage-related element or a panel of isolated tails of the invention are capable of assembling to form a chimeric particle of the invention.

[0423] The first and second pharmaceutical compositions are typically stored in separate containers.

[0424] The first and second phage, phage satellite or phage-related element are different, and are capable of assembling to form a chimeric infectious particle of the invention.

[0425] A kit of parts may comprise two or more first compositions each comprising a different capsid. Alternatively, or in addition, said kit may comprise two or more second compositions each comprising a different tail.

[0426] A kit of parts may further comprise instructions for use.

[0427] Nucleic acids, expression cassettes and expression vectors

[0428] The invention further provides a nucleic acid comprising or consisting of (a) a nucleotide sequence encoding a capsid from a first phage, phage satellite or phage-related element; and / or (b) a nucleotide sequence encoding a tail from a second phage, phage satellite or phage-related element; wherein the first and second phage, phage satellite or phage-related element are different, wherein the capsid and the tail are capable of assembling to form a chimeric infectious particle of the invention.

[0429] The nucleic acid may comprise or consist of both (a) a nucleotide sequence encoding a capsid from a first phage, phage satellite or phage-related element; and (b) a nucleotide sequence encoding a tail from a second phage, phage satellite or phage-related element.

[0430] The nucleotide sequence encoding the capsid may be operably linked to a promoter. Alternatively, or in addition, the nucleotide sequence encoding the tail may be operably linked to a promoter. Any appropriate promoter may be used. Suitable promoters, including phage promoters are known in the art and may be readily selected by one of ordinary skill without undue burden.The nucleotide sequence encoding the capsid and / or the nucleotide sequence encoding the tail may be comprised in a polycistronic cassette; with a single promoter driving expression of all components of the cassette.

[0431] A nucleic acid may further comprise or consist of a nucleic acid sequence which will be contained within the capsid of the chimeric particle, i.e. a nucleic acid sequence which will form the genome of the chimeric particle. Non-limiting examples of such genomes are described herein.

[0432] The invention also provides an expression vector comprising a nucleic acid as defined herein. Non-limiting examples of expression vectors include plasmids and other expression cassettes.

[0433] As used herein, the term "plasmid", refers to an extra-chromosomal DNA molecule separate from the chromosomal DNA which is capable of replicating independently of the chromosomal DNA. Preferably a plasmid is circular and may be double-stranded.

[0434] The terms "nucleic acid cassette”, “nucleic acid construct", "expression cassette" and "nucleic acid expression cassette" are used interchangeably to mean a nucleic acid molecule that is capable of directing transcription. A nucleic acid cassette includes, at the least, a promoter or a structure functionally equivalent to a promoter and a nucleic acid sequence to be transcribed. Thus, a nucleic acid cassette includes, at the least, a promoter or a structure functionally equivalent to a promoter and a nucleic acid sequence encoding a protein of interest. In the present invention, a nucleic acid cassette includes, at the least, a promoter or a structure functionally equivalent to a promoter, a nucleic acid sequence encoding a signal peptide and a nucleic acid encoding a therapeutic protein. A nucleic acid cassette may include additional elements, such as an enhancer, and / or a transcription termination signal.

[0435] A nucleic acid, or a nucleic acid sequence comprised within a nucleic acid or an expression vector / cassette may comprise one or more codon-optimised gene, which is optimised for expression in a host or target cell, as described herein.

[0436] Cells

[0437] The invention also provides a host cell comprising a nucleic acid or an expression vector as described herein. Said host cell is typically a bacterial cell, particularly a bacterial cell which (i) can be infected by a chimeric particle of the invention; and / or (i) which is permissive for production and / or replication of a chimeric particle of the invention.

[0438] A bacterial cell of the invention may comprise a single nucleic acid or expression vector encoding the capsid. A bacterial cell of the invention may comprise a single nucleic acid or expression vector encoding the tail. A bacterial cell of the invention may comprise a single nucleic acid or expression vector encoding the capsid and the tail. A bacterial cell of the invention may comprise a first nucleic acid or expression vector encoding the capsid and asecond nucleic acid or expression vector encoding the phage tail. Said nucleic acid or expression vector may further comprise a nucleic acid sequence which will be contained within the capsid of the chimeric particle, i.e. the genome of the chimeric particle.

[0439] As described herein, the invention further provides a pharmaceutical formulation which comprises a bacterial cell of the invention and at least one pharmaceutically acceptable carrier, excipient, buffer or diluent.

[0440] Methods of production

[0441] The invention also provides a method of producing a chimeric infectious particle of the invention.

[0442] A method of producing a chimeric infectious particle of the invention method may comprise or consist of culturing a bacterial cell of the invention under conditions for production of a chimeric infectious particle. Optionally said method further comprises purifying the resulting chimeric particle.

[0443] Alternatively, a method of producing a chimeric infectious particle of the invention method may comprise or consist of the following steps: (a) culturing a first bacterial cell of the invention to produce the capsid under conditions for production of the capsid; (b) culturing a second bacterial cell of the invention to produce the phage tail under conditions for production of the phage tail; and (c) combining the capsid produced in step (a) with the phage tail produced in step (b) to form a chimeric particle. Optionally said method further comprises purifying the capsid, phage tail and / or chimeric particle.

[0444] The method of the invention may comprise the use of codon-optimised genes, nucleic acids and / or expression vectors, as described herein.

[0445] The method of the invention may be a scalable GMP-compatible method. Thus, the method of the invention typically allows the generation of high titre purified chimeric particles.

[0446] The present invention also provides a method of producing the chimeric infectious particles of the invention, wherein the method comprises contacting an isolated capsid from a first phage, phage satellite or phage-related element with an isolated tail from a second phage, phage satellite or phage-related element in conditions that allow for the assembly of the capsid and the tail to result in a chimeric infectious particle. This method enables the formation of chimeric infectious particles of the invention using standard in vitro methods and isolated capsids and tails from different phages, phage satellites and / or phage-related elements. This surprising modularity is exemplified in the present application and provides the skilled person with an extensive array of combinations of capsids and tails from isolated phages, phage satellites and / or phage-related elements.

[0447] This method of producing chimeric infectious particles of the invention can comprise the use of tail-less capsids of the invention as the isolated capsid from a first phage, phagesatellite or phage-related element. Alternatively or in addition, the method of producing chimeric infectious particles of the invention can comprise the use of isolated tails of the invention as described herein. The resulting chimeric infectious particles may be as described herein.

[0448] Chimeric infectious particles produced by this method may be isolated and / or purified for further use. In particular, such isolation and / or purification may be desirable in the context of therapeutic uses, where purification may be needed to comply with GMP practices in the production of therapeutic and / or pharmaceutic formulations for use in humans or animals.

[0449] The invention also provides chimeric infectious particles produced by a method of the invention. Such particles may be any as described herein.

[0450] Therapy

[0451] The invention provides a chimeric infectious particle or population thereof, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention for use in a method of therapy.

[0452] As described and exemplified herein, the present inventors have demonstrated for the first time that isolated tails from phage are able to bind to bacteria and subsequently recruit tail-less capsids (see Example 15). Accordingly, the invention further provides (i) a tail-less capsid from a first phage, phage satellite or phage-related element or a panel of tail-less capsids of the invention; and (ii) an isolated tail from a second phage, phage satellite or phage-related element or a panel of isolated tails of the invention; for use in a method of therapy. Typically, said method comprises (a) administering a therapeutically effective amount of the isolated tail or the panel of isolated tails to a subject in need thereof; and (b) subsequently administering a therapeutically effective amount of the tail-less capsid or the panel of tail-less capsids to the subject in need thereof. In some embodiments, step (b) is performed no more than about 24h after step (a), no more than about 12h after step (a), no more than about 8h after step (a), no more than about 4h after step (a), no more than about 2h after step (a) or no more than about 1h after step (a).

[0453] The therapy according to the invention may be for treating any subject such as described herein, preferably a mammalian subject, more preferably a human subject.

[0454] The therapy may be for (a) treating and / or preventing a bacterial infection; and / or (b) modulating the gut microbiome to improve digestion and / or immunity.

[0455] The invention provides a chimeric infectious particle or population thereof, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention for use in a method of treating and / or preventing a bacterial infection. Said bacterial infection may be selected from the group of respiratory infections, urinary tract infections, skin and soft tissue infections, bloodstream infections (sepsis),gastrointestinal infections, bone and joint infections (osteomyelitis, septic arthritis), meningitis, endocarditis, wound infections, peritonitis, otitis media, sinusitis, dental infections (abscesses), pelvic inflammatory disease, eye infections (conjunctivitis, keratitis), infections that are generated by Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis, Pseudomonas aeruginosa, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, Clostridium difficile, Shigella spp., Vibrio cholerae, Kingella kingae, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus viridans, Enterococcus faecalis, Bacteroides fragilis, Moraxella catarrhalis, Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Chlamydia trachomatis or other relevant pathogens and / or multiple drug resistant bacterial infection.

[0456] The invention further provides (i) a tail-less capsid from a first phage, phage satellite or phage-related element or a panel of tail-less capsids of the invention; and (ii) an isolated tail from a second phage, phage satellite or phage-related element or a panel of isolated tails of the invention for use in a method of treating and / or preventing a bacterial infection. Typically, said method comprises (a) administering a therapeutically effective amount of the isolated tail or the panel of isolated tails to a subject in need thereof; and (b) subsequently administering a therapeutically effective amount of the tail-less capsid or the panel of tail-less capsids to the subject in need thereof. In some embodiments, step (b) is performed no more than about 24h after step (a), no more than about 12h after step (a), no more than about 8h after step (a), no more than about 4h after step (a), no more than about 2h after step (a) or no more than about 1h after step (a). Said bacterial infection may be selected from the group of respiratory infections, urinary tract infections, skin and soft tissue infections, bloodstream infections (sepsis), gastrointestinal infections, bone and joint infections (osteomyelitis, septic arthritis), meningitis, endocarditis, wound infections, peritonitis, otitis media, sinusitis, dental infections (abscesses), pelvic inflammatory disease, eye infections (conjunctivitis, keratitis), infections that are generated by Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis, Pseudomonas aeruginosa, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, Clostridium difficile, Shigella spp., Vibrio cholerae, Kingella kingae, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus viridans, Enterococcus faecalis, Bacteroides fragilis, Moraxella catarrhalis, Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Chlamydia trachomatis or other relevant pathogens and / or multiple drug resistant bacterial infection.

[0457] The invention provides a method of treatment comprising administering a therapeutically effective amount of a chimeric infectious particle or population thereof, a panel,a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention to a subject in need thereof.

[0458] The subject may be any subject, as defined herein. In particular the subject may be mammalian subject, more preferably a human subject.

[0459] The method of treatment may be for (a) treating and / or preventing a bacterial infection; and / or (b) modulating the gut microbiome to improve digestion and / or immunity.

[0460] The invention provides a method of treating and / or preventing a bacterial infection comprising administering a therapeutically effective amount of a chimeric infectious particle or population thereof, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention to a subject in need thereof. Said bacterial infection may be selected from the group of respiratory infections, urinary tract infections, skin and soft tissue infections, bloodstream infections (sepsis), gastrointestinal infections, bone and joint infections (osteomyelitis, septic arthritis), meningitis, endocarditis, wound infections, peritonitis, otitis media, sinusitis, dental infections (abscesses), pelvic inflammatory disease, eye infections (conjunctivitis, keratitis), infections that are generated by Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis, Pseudomonas aeruginosa, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, Clostridium difficile, Shigella spp., Vibrio cholerae, Kingella kingae, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus viridans, Enterococcus faecalis, Bacteroides fragilis, Moraxella catarrhalis, Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Chlamydia trachomatis or other relevant pathogens and / or multiple drug resistant bacterial infection.

[0461] The invention provides a method of treating and / or preventing a bacterial infection comprising administering a therapeutically effective amount of (i) a tail-less capsid from a first phage, phage satellite or phage-related element or a panel of tail-less capsids of the invention; and (ii) an isolated tail from a second phage, phage satellite or phage-related element or a panel of isolated tails of the invention to a subject in need thereof. Typically, said method comprises (a) administering a therapeutically effective amount of the isolated tail or the panel of isolated tails to a subject in need thereof; and (b) subsequently administering a therapeutically effective amount of the tail-less capsid or the panel of tail-less capsids to the subject in need thereof. In some embodiments, step (b) is performed no more than about 24h after step (a), no more than about 12h after step (a), no more than about 8h after step (a), no more than about 4h after step (a), no more than about 2h after step (a) or no more than about 1h after step (a). Said bacterial infection may be selected from the group of respiratory infections, urinary tract infections, skin and soft tissue infections, bloodstream infections (sepsis), gastrointestinal infections, bone and joint infections (osteomyelitis, septic arthritis),meningitis, endocarditis, wound infections, peritonitis, otitis media, sinusitis, dental infections (abscesses), pelvic inflammatory disease, eye infections (conjunctivitis, keratitis), infections that are generated by Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis, Pseudomonas aeruginosa, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, Clostridium difficile, Shigella spp., Vibrio cholerae, Kingella kingae, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus viridans, Enterococcus faecalis, Bacteroides fragilis, Moraxella catarrhalis, Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Chlamydia trachomatis or other relevant pathogens and / or multiple drug resistant bacterial infection.

[0462] Also provided is the use of a chimeric infectious particle or population thereof, a panel, a nucleic acid, an expression vector, a tail-less capsid, an isolated tail, and / or a bacterial cell of the invention in the manufacture of a medicament. The medicament may be for use in (a) treating and / or preventing a bacterial infection (e.g. those described herein); and / or (b) modulating the gut microbiome to improve digestion and / or immunity.

[0463] As described herein, other therapeutic genes may be included in the genome of chimeric particles of the invention. In particular, antigen presenting genes, drugs, biofilm degrading genes, etc. Therefore, a chimeric infectious particle or population thereof, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be used in the treatment of a wide range of diseases or disorders, depending on the therapeutic gene comprised in the chimeric particle. By way of non-limiting example, a chimeric infectious particle or population thereof, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be used as a phage vaccine. By way of a further non-limiting example, a chimeric infectious particle or population thereof, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be used in a method of treating and / or preventing cancer and other genetic diseases.

[0464] A chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be administered by any appropriate route.

[0465] Administration of a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention is generally by conventional routes e.g. intravenous, subcutaneous, intraperitoneal, or mucosal routes. The administration may be by parenteral injection, for example, a subcutaneous, intradermal or intramuscular injection. For example, compounds, drug delivery systems and compositions and formulations comprising compounds of the invention may be particularly suited to administration intravenously,intramuscularly, intradermally, or subcutaneously. Administration of chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be particularly suited to administration by injection, such as intravenously, intramuscularly, intradermally, or subcutaneously, or by oral administration. A chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be for oral, buccal, nasal, rectal, transdermal, intravenous, intramuscular or ocular administration, particularly oral administration.

[0466] A chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid prior to injection may alternatively be prepared. The preparation may also be emulsified.

[0467] A chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and / or adjuvants which enhance the effectiveness of the vaccine.

[0468] Formulation of a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may therefore be adapted using routine practice to suit the preferred route of administration.

[0469] Generally, the carrier is a pharmaceutically-acceptable carrier. Non-limiting examples of pharmaceutically acceptable carriers include water, saline, and phosphate-buffered saline. In some embodiments, however, where the composition comprises a compound of the invention, this may be in lyophilised form, in which case it may include a stabiliser, such as BSA. In some embodiments, it may be desirable to formulate the composition with a preservative, such as thiomersal or sodium azide, to facilitate long term storage.

[0470] Examples of additional adjuvants which may be effective include but are not limited to: complete Freunds adjuvant (CFA), Incomplete Freunds adjuvant (IFA), Saponin, a purified extract fraction of Saponin such as Quil A, a derivative of Saponin such as QS-21, lipid particles based on Saponin such as ISCOM / ISCOMATRIX, E. coli heat labile toxin (LT) mutants such as LTK63 and / or LTK72, aluminium hydroxide, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine (CGP 11637, referred to as nor-MDP), N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1'-2'-dipalmitoyl-sn-glycero-3-hydroxyphosphoryl oxy)-ethylamine (CGP 19835 A, referred to as MTP-PE), and RIBI, which contains three components extracted from bacteria, monophosphoryl lipid A, trehalose dimycolate and cell wall skeleton (MPL+TDM+CWS) in a 2 % squalene / Tween 80 emulsion, the MF59 formulation developed by Novartis, and the AS02, AS01, AS03 and AS04 adjuvant formulations developed by GSK Biologicals (Rixensart, Belgium).

[0471] Examples of buffering agents include, but are not limited to, sodium succinate (pH 6.5), and phosphate buffered saline (PBS; pH 6.5 and 7.5).

[0472] Additional formulations which are suitable for other modes of administration include suppositories, eye drops and, in some cases, oral formulations or formulations suitable for distribution as aerosols. For suppositories, traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1%-2%.

[0473] Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.

[0474] In some cases, after an initial administration a subsequent administration of a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be performed. The administration may, for instance, be at least a week, two weeks, a month, two months, six months, a year or more after the initial administration. In some instances, a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may be administered at least once daily, twice a week, once a week, once a fortnight, once a month, every two months, every six months, annually or at longer intervals. A chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention may, for instance, be administered at intervals dictated by when the effects of the previous administration are decreasing.

[0475] The invention provides a method of treatment comprising the step of: (a) identifying the pathologic bacterial species and / or strains present in a subject; and (b) providing a therapeutically effective amount of a chimeric infectious particle or population thereof, a tailless capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell or a pharmaceutical formulation of the invention to the subject, which chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, panel, nucleic acid, expression vector,bacterial cell, or pharmaceutical formulation of the invention targets the identified pathologic bacterial species and / or strains present in the subject. Wherein said therapy comprises the use of tail-less capsids and isolated tails, the tail-less capsids may be administered subsequently to the isolated tails, as described herein. Said method of treatment may comprise a method or step of identifying the pathologic bacterial species and / or strains present in the subject by a diagnostic or detection method as described herein.

[0476] Diagnostic methods

[0477] The invention provides a method of diagnosing infection with a bacterial species and / or bacterial strain of interest, or a method of detecting the presence of an infection by a bacterial species and / or bacterial strain of interest in a sample. Such methods may comprise or consist of the following steps: (a) contacting a sample obtained from a subject with a chimeric infectious particle or population thereof, a panel, a nucleic acid, an expression vector, a bacterial cell, a kit of parts or a pharmaceutical formulation of the invention, wherein the chimeric particle comprises a nucleic acid molecule comprising a reporter gene or encoding a reporter protein; and (b) detecting the reporter gene or protein. Typically, a positive signal for the reporter gene or protein indicates the presence of an infection by a bacterial species and / or strain which is susceptible to infection by the chimeric particle. In said method, optionally two or more different chimeric particles capable of infecting different bacterial species and / or strains are used, said two or more different chimeric particles each comprising a nucleic acid molecule comprising a different reporter gene or encoding a different reporter protein, such that the different bacterial species and / or strains can be differentiated based on the reporter gene or protein detected. A method of diagnosing infection with a bacterial species and / or bacterial strain of interest, or a method of detecting the presence of an infection by a bacterial species and / or bacterial strain of interest in a sample according to the invention may further comprise a method of treating the subject. In particular, a method of diagnosing infection with a bacterial species and / or bacterial strain of interest, or a method of detecting the presence of an infection by a bacterial species and / or bacterial strain of interest in a sample according to the invention may further comprise a step of administering a therapeutically effective amount of a treatment for the bacterial species and / or bacterial strain detected within the sample.

[0478] The invention further provides a method of diagnosing infection with a bacterial species and / or bacterial strain of interest, or a method of detecting the presence of an infection by a bacterial species and / or bacterial strain of interest in a sample. Such methods may comprise or consist of the following steps: (a) contacting a sample obtained from a subject with an isolated tail or panel of isolated tails of the invention; (b) contacting the sample with a tail-less capsid or panel of tail-less capsids of the invention, wherein the tail-less capsid or panel of tail-less capsids of the invention comprises a nucleic acid molecule comprising a reporter geneor encoding a reporter protein; and (c) detecting the reporter gene or protein. Typically, a positive signal for the reporter gene or protein indicates the presence of an infection by a bacterial species and / or strain which is susceptible to infection by the chimeric particle. In said method, optionally two or more different tail-less capsids capable of infecting different bacterial species and / or strains are used, said two or more different tail-less capsids each comprising a nucleic acid molecule comprising a different reporter gene or encoding a different reporter protein, such that the different bacterial species and / or strains can be differentiated based on the reporter gene or protein detected. Optionally the sample may be washed at least one, at least twice or at least three times, between steps (a) and (b).

[0479] A method of diagnosing infection with a bacterial species and / or bacterial strain of interest, or a method of detecting the presence of an infection by a bacterial species and / or bacterial strain of interest in a sample according to the invention may further comprise a method of treating the subject. In particular, a method of diagnosing infection with a bacterial species and / or bacterial strain of interest, or a method of detecting the presence of an infection by a bacterial species and / or bacterial strain of interest in a sample according to the invention may further comprise a step of administering a therapeutically effective amount of a treatment for the bacterial species and / or bacterial strain detected within the sample.

[0480] Applications

[0481] In recent years, there is growing interest in the use of phage in a wide range of sectors, particularly in animal, environmental and human health.

[0482] The chimeric infectious particles or populations thereof, tail-less capsids, isolated tails, panels, nucleic acids, expression vectors, bacterial cells, compositions, kits of parts and pharmaceutical formulations of the invention have the potential to be used in a wide range of applications, and in particular in applications where phage are already in use, or where the use of phage is envisaged or under development.

[0483] Accordingly, the invention provides a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation as described herein for use in drug discovery and drug discovery programs, in particular in the field of antimicrobial research. The method of diagnosis of the invention may be used to assist in the research of novel antibiotics on the efficacy of such antibiotics. As such, the chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, composition, kit of parts or pharmaceutical formulation of the invention may be used in vitro or in vivo in drug discovery, especially in studies requiring the monitoring of bacterial populations.The invention also a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation as described herein for use in the antibacterial treatment of agricultural products, in particular foodstuffs and animal feed. The chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, composition, kit of parts or pharmaceutical formulation may be applied to such agricultural products with known techniques to the person skilled in the art. The efficacy of the antibacterial treatment of agricultural products may be assessed using the method of or detection of the invention or any other known method in the art. It will be appreciated that any contemplated application of the chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, composition, kit of parts or pharmaceutical formulation of the invention in the field of food safety is also encompassed by the present invention.

[0484] The invention further provides a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation of the invention for use in the decontamination of contaminated environments. This is especially relevant for sensitive environment that needs to stay sterile or that are in contact with subjects or products for use or consumption by subjects susceptible to bacterial infection. By way of non-limiting examples, the sensitive environment may be clinical environments, food-processing environments or water distribution systems.

[0485] The invention further provides a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation of the invention for use in the degradation of biofilms. This is particularly relevant for situations when a subject may have contracted a bacterial infection which leads to the formation of a biofilm that is resistant to conventional antibiotics therapies. Alternatively, or additionally, the chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, composition, kit of parts or pharmaceutical formulation may be use for prevention of biofilm formation in a prophylactic manner.

[0486] The invention further provides a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation of the invention for use in controlling plant diseases. Bacterial infection of plants may lead to steep reduction in crop yields and crop quality. The chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, kit of parts or pharmaceutical formulation may be applied plants and crops with known techniques to the person skilled inthe art. The chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, composition, kit of parts or pharmaceutical formulation are therefore also provided for use in improving plant yield.

[0487] The invention further provides a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation of the invention for use in disinfecting water sources. This is particularly relevant for water sources for human and animal consumption which may be bacterially infected. Water bacterial infection may lead to severe disorders in human and animals. The chimeric infectious particle or population thereof, tailless capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, kit of parts or pharmaceutical formulation of the invention may therefore also be used in prophylactic control of bacterial infection of water sources by regular administration to prevent bacterial infection, in particular in regions where endemic bacterial infections are present.

[0488] The invention further provides a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation of the invention for use in research.

[0489] The invention further provides a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation of the invention for use in biodefence. Potential bioweapon may be using engineered bacterial agents that the methods of diagnosis and / or detection of the invention may be used to identify and subsequently to treat using the chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, kit of parts or pharmaceutical formulation of the invention. Without being bound by theory, it is believed that the chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, kit of parts or pharmaceutical formulation of the invention provides an adaptable tool to respond rapidly and efficiently to such threats.

[0490] The invention further provides a chimeric infectious particle or population thereof, a tail-less capsid, an isolated tail, a panel, a nucleic acid, an expression vector, a bacterial cell, a composition, a kit of parts or a pharmaceutical formulation of the invention for use in nanotechnology. By way of example, the combination of nanotechnology and phages or phage-like particle has known potential to provide tools for the rapid and accurate detection and treatment of bacteria in biological samples. The chimeric infectious particle or population thereof, tail-less capsid, isolated tail, panel, nucleic acid, expression vector, bacterial cell, kit of parts or pharmaceutical formulation of the invention may be integrated in nanomaterial to facilitate methods of diagnostics and / or detection according to the invention. Such uses maybe applied to several applications such as nanomaterial templates or developing drug delivery systems.

[0491] SEQUENCE HOMOLOGY

[0492] Any of a variety of sequence alignment methods can be used to determine percent identity, including, without limitation, global methods, local methods and hybrid methods, such as, e.g., segment approach methods. Protocols to determine percent identity are routine procedures within the scope of one skilled in the art. Global methods align sequences from the beginning to the end of the molecule and determine the best alignment by adding up scores of individual residue pairs and by imposing gap penalties. Non-limiting methods include, e.g., CLUSTAL W, see, e.g., Julie D. Thompson et al., CLUSTAL W: Improving the Sensitivity of Progressive Multiple Sequence Alignment Through Sequence Weighting, Position- Specific Gap Penalties and Weight Matrix Choice, 22(22) Nucleic Acids Research 4673-4680 (1994); and iterative refinement, see, e.g., Osamu Gotoh, Significant Improvement in Accuracy of Multiple Protein. Sequence Alignments by Iterative Refinement as Assessed by Reference to Structural Alignments, 264(4) J. Mol. Biol. 823-838 (1996). Local methods align sequences by identifying one or more conserved motifs shared by all of the input sequences. Non-limiting methods include, e.g., Match-box, see, e.g., Eric Depiereux and Ernest Feytmans, Match-Box: A Fundamentally New Algorithm for the Simultaneous Alignment of Several Protein Sequences, 8(5) CABIOS 501 -509 (1992); Gibbs sampling, see, e.g., C. E. Lawrence et al., Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment, 262(5131 ) Science 208-214 (1993); Align-M, see, e.g., Ivo Van Walle et al., Align-M - A New Algorithm for Multiple Alignment of Highly Divergent Sequences, 20(9) Bioinformatics: 1428- 1435 (2004).

[0493] Thus, percent sequence identity is determined by conventional methods. See, for example, Altschul et al., Bull. Math. Bio. 48: 603-16, 1986 and Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915-19, 1992. Briefly, two amino acid sequences are aligned to optimise the alignment scores using a gap opening penalty of 10, a gap extension penalty of 1, and the "blosum 62" scoring matrix of Henikoff and Henikoff (ibid.) as shown below (amino acids are indicated by the standard one-letter codes).

[0494] The "percent sequence identity" between two or more nucleic acid or amino acid sequences is a function of the number of identical positions shared by the sequences. Thus, % identity may be calculated as the number of identical nucleotides / amino acids divided bythe total number of nucleotides / amino acids, multiplied by 100. Calculations of % sequence identity may also take into account the number of gaps, and the length of each gap that needs to be introduced to optimise alignment of two or more sequences. Sequence comparisons andthe determination of percent identity between two or more sequences can be carried out using specific mathematical algorithms, such as BLAST, which will be familiar to a skilled person.

[0495] ALIGNMENT SCORES FOR DETERMINING SEQUENCE IDENTITY A R N D C Q E G H I L K M F P S T WY V

[0496] A4

[0497] R -1 5

[0498] N -2 0 6

[0499] D -2 -2 1 6

[0500] C 0 -3 -3 -3 9

[0501] Q -1 1 0 0 -3 5

[0502] E -1 0 0 2 -4 2 5

[0503] G O -2 0 -1 -3 -2 -2 6

[0504] H -2 0 1 -1 -3 0 0 -2 8

[0505] 1 -1 -3 -3 -3 -1 -3 -3 -4 -3 4

[0506] L -1 -2 -3 -4 -1 -2 -3 -4 -3 2 4

[0507] K -1 2 0 -1 -3 1 1 -2 -1 -3 -2 5

[0508] M -1 -1 -2 -3 -1 0 -2 -3 -2 1 2 -1 5

[0509] F -2 -3 -3 -3 -2 -3 -3 -3 -1 0 0 -3 0 6

[0510] P -1 -2 -2 -1 -3 -1 -1 -2 -2 -3 -3 -1 -2 -4 7

[0511] S 1 -1 1 0 -1 0 0 0 -1 -2 -2 0 -1 -2 -1 4

[0512] T 0 -1 0 -1 -1 -1 -1 -2 -2 -1 -1 -1 -1 -2 -1 1 5

[0513] W -3 -3 -4 -4 -2 -2 -3 -2 -2 -3 -2 -3 -1 1 -4 -3 -2 11

[0514] Y -2 -2 -2 -3 -2 -1 -2 -3 2 -1 -1 -2 -1 3 -3 -2 -2 2 7

[0515] V 0 -3 -3 -3 -1 -2 -2 -3 -3 3 1 -2 1 -1 -2 -2 0 -3 -1 4

[0516] The percent identity is then calculated as:

[0517] Total number of identical matches

[0518] > x 100

[0519] [length of the longer sequence plus the

[0520] number of gaps introduced into the longer

[0521] sequence in order to align the two sequences]

[0522] Substantially homologous polypeptides are characterised as having one or more amino acid substitutions, deletions or additions. These changes are preferably of a minor nature, that is conservative amino acid substitutions (as described herein) and othersubstitutions that do not significantly affect the folding or activity of the polypeptide; small deletions, typically of one to about 30 amino acids; and small amino- or carboxyl-terminal extensions, such as an amino-terminal methionine residue, a small linker peptide of up to about 20-25 residues, or an affinity tag.

[0523] In addition to the 20 standard amino acids, non-standard amino acids (such as 4-hydroxyproline, 6-N-methyl lysine, 2-aminoisobutyric acid, isovaline and a -methyl serine) may be substituted for amino acid residues of the polypeptides of the present invention. A limited number of non-conservative amino acids, amino acids that are not encoded by the genetic code, and unnatural amino acids may be substituted for polypeptide amino acid residues. The polypeptides of the present invention can also comprise non-naturally occurring amino acid residues.

[0524] Non-naturally occurring amino acids include, without limitation, trans-3-methylproline, 2,4-methano-proline, cis-4-hydroxyproline, trans-4-hydroxy-proline, N-methylglycine, allothreonine, methyl-threonine, hydroxy-ethylcysteine, hydroxyethylhomo-cysteine, nitroglutamine, homoglutamine, pipecolic acid, tert-leucine, norvaline, 2-azaphenylalanine, 3-azaphenyl-alanine, 4-azaphenyl-alanine, and 4-fluorophenylalanine. Several methods are known in the art for incorporating non-naturally occurring amino acid residues into proteins. For example, an in vitro system can be employed wherein nonsense mutations are suppressed using chemically aminoacylated suppressor tRNAs. Methods for synthesising amino acids and aminoacylating tRNA are known in the art. Transcription and translation of plasmids containing nonsense mutations is carried out in a cell free system comprising an E. coli S30 extract and commercially available enzymes and other reagents. Proteins are purified by chromatography. See, for example, Robertson et al., J. Am. Chem. Soc. 113:2722, 1991; Ellman et al., Methods Enzymol. 202:301, 1991; Chung et al., Science 259:806-9, 1993; and Chung et al., Proc. Natl. Acad. Sci. USA 90:10145-9, 1993). In a second method, translation is carried out in Xenopus oocytes by microinjection of mutated mRNA and chemically aminoacylated suppressor tRNAs (Turcatti et al., J. Biol. Chem. 271:19991-8, 1996). Within a third method, E. coli cells are cultured in the absence of a natural amino acid that is to be replaced (e.g., phenylalanine) and in the presence of the desired non-naturally occurring amino acid(s) (e.g., 2-azaphenylalanine, 3-azaphenylalanine, 4-azaphenylalanine, or 4-fluorophenylalanine). The non-naturally occurring amino acid is incorporated into the polypeptide in place of its natural counterpart. See, Koide et al., Biochem. 33:7470-6, 1994. Naturally occurring amino acid residues can be converted to non-naturally occurring species by in vitro chemical modification. Chemical modification can be combined with site-directed mutagenesis to further expand the range of substitutions (Wynn and Richards, Protein Sci.

[0525] 2:395-403, 1993).A limited number of non-conservative amino acids, amino acids that are not encoded by the genetic code, non-naturally occurring amino acids, and unnatural amino acids may be substituted for amino acid residues of polypeptides of the present invention.

[0526] Essential amino acids in the polypeptides of the present invention can be identified according to procedures known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham and Wells, Science 244: 1081-5, 1989). Sites of biological interaction can also be determined by physical analysis of structure, as determined by such techniques as nuclear magnetic resonance, crystallography, electron diffraction or photoaffinity labeling, in conjunction with mutation of putative contact site amino acids. See, for example, de Vos et al., Science 255:306-12, 1992; Smith et al., J. Mol. Biol. 224:899-904, 1992; Wlodaver et al., FEBS Lett. 309:59-64, 1992. The identities of essential amino acids can also be inferred from analysis of homologies with related components (e.g. the translocation or protease components) of the polypeptides of the present invention.

[0527] Multiple amino acid substitutions can be made and tested using known methods of mutagenesis and screening, such as those disclosed by Reidhaar-Olson and Sauer (Science 241:53-7, 1988) or Bowie and Sauer (Proc. Natl. Acad. Sci. USA 86:2152-6, 1989). Briefly, these authors disclose methods for simultaneously randomising two or more positions in a polypeptide, selecting for functional polypeptide, and then sequencing the mutagenised polypeptides to determine the spectrum of allowable substitutions at each position. Other methods that can be used include phage display (e.g., Lowman et al., Biochem. 30:10832-7, 1991; Ladner et al., U. S. Patent No. 5,223,409; Huse, WIPO Publication WO 92 / 06204) and region-directed mutagenesis (Derbyshire et al., Gene 46:145, 1986; Ner et al., DNA 7:127, 1988).

[0528] Multiple amino acid substitutions can be made and tested using known methods of mutagenesis and screening, such as those disclosed by Reidhaar-Olson and Sauer (Science 241:53-7, 1988) or Bowie and Sauer (Proc. Natl. Acad. Sci. USA 86:2152-6, 1989). Briefly, these authors disclose methods for simultaneously randomising two or more positions in a polypeptide, selecting for functional polypeptide, and then sequencing the mutagenised polypeptides to determine the spectrum of allowable substitutions at each position. Other methods that can be used include phage display (e.g., Lowman et al., Biochem. 30:10832-7, 1991; Ladner et al., U. S. Patent No. 5,223,409; Huse, WIPO Publication WO 92 / 06204) and region-directed mutagenesis (Derbyshire et al., Gene 46:145, 1986; Ner et al., DNA 7:127, 1988).

[0529] SEQUENCE INFORMATIONKey to sequences

[0530] SEQ ID NO: 1 KpCIDSM30104 immature capsid protein

[0531] SEQ ID NO: 2 EcCIGN02175 immature capsid protein

[0532] SEQ ID NO: 3 EcCIEDL933 immature capsid protein

[0533] SEQ ID NO: 4 HK022 immature capsid protein

[0534] SEQ ID NO: 5 HK022 immature capsid protein

[0535] SEQ ID NO: 6 lambda phage immature capsid protein

[0536] SEQ ID NO: 7 phage 80 immature capsid protein

[0537] SEQ ID NO: 8 KpCIDSM30104 adaptor protein

[0538] SEQ ID NO: 9 EcCIGN02175 adaptor protein

[0539] SEQ ID NO: 10 EcCIEDL933 adaptor protein

[0540] SEQ ID NO: 11 HK106 adaptor protein

[0541] SEQ ID NO: 12 HK022 adaptor protein

[0542] SEQ ID NO: 13 KpCIDSM30104 connector protein

[0543] SEQ ID NO: 14 EcCIGN02175 connector protein

[0544] SEQ ID NO: 15 EcCIEDL933 connector protein

[0545] SEQ ID NO: 16 HK106 connector protein

[0546] SEQ ID NO: 17 HK022 connector protein

[0547] SEQ ID NO: 18 phage 80 neck protein

[0548] SEQ ID NO: 19 lambda phage tail protein

[0549] SEQ ID NO: 20 HK022 major tail protein

[0550] SEQ ID NO: 21 HK106 major tail protein

[0551] SEQ ID NO: 22 Ehh18_phi2 major tail (high possible donor)

[0552] SEQ ID NO: 23 Ehh18_phi5 major tail (high possible donor)

[0553] SEQ ID NO: 24 Ehh18_phi1 major tail (possible donor)

[0554] SEQ ID NO: 25 lambda phage neck protein

[0555] SEQ ID NO: 26 phage 80 tail protein

[0556] SEQ ID NO: 27 HK022 tail tape measure protein

[0557] SEQ ID NO: 28 HK106 tail tape measure protein

[0558] SEQ ID NO: 29 phi2 tail tape measure protein (high possible donor)

[0559] SEQ ID NO: 30 phi5 tail tape measure protein (high possible donor)

[0560] SEQ ID NO: 31 phi 1 tail tape tail tape measure protein (possible donor)

[0561] SEQ ID NO: 32 phage 80 tail tape measure protein

[0562] SEQ ID NO: 33 lambda phage tail tape measure protein

[0563] SEQ ID NO: 34 consensus N-terminal motif shared by mature capsid proteins of cf-PICI and phage (identified in EcCIEDL933 and HK97)SEQ ID NO: 35 KpCIDSM30104 portal protein

[0564] SEQ ID NO: 36 EcCIGN02175 portal protein

[0565] SEQ ID NO: 37 EcCIEDL933 portal protein

[0566] Sequences

[0567] Where an initial Met amino acid residue ora corresponding initial codon is indicated in any of the following amino acid SEQ ID NOs, said residue / codon is optional.

[0568] SEQ ID NO: 1 KpCIDSM30104 immature capsid protein MKKLLELRQQKAALKTQMRSMLDKADTEKRSLNEEEGKKFDELRAQADALEVEINRLEAVAEDQRNLP GTSVEGDPVSNDELRHYIMTGDTRSLSTLVQADGGYTVIPELDKEIMRQLQDDSVMRSIATVKTTKTN EYQKLVSVGGTTVNRGTEGEARTETSTPKMERVDIKLNPIYAYPKTTQEILDFSEVDILGWLSSEIAD TFTATEESDFVNGDGDKKSKGFLSYPRAATADKTRPFGTLEKMEAADVSSDGLIDLLYKLKAKYRKNA VWVMNSNTAAKLQKLKNGNGDYIWRDRLVAGSPDTLLGRPVQYLETMPDADAGEAFLAVGDFKRGYFI VDHTTGVRTRPDNITEPGFYKVHTDKYLGGGWDSNAIKILELAGS*

[0569] SEQ ID NO: 2 EcCIGN02175 immature capsid protein MKKLLELRQQKAALKTQMRSMLDKADTEKRSLNEEEGQKFDELRAQADALEVEITRLEAVADDQRNLP GTSVEGEPVSNDELRHYIMTGDTRSLSTLVQADGGYTVIHELDKEIMRQLQDDSVMRSIATVKTTKTN EYQKLVSVGGTTVNRGTEGEARTETSTPKMERVDIKLNPIYAYPKTTQEILDFSEVDILGWLSSEIAD TFTATEESDFVNGDGDKKSKGFLSYPRAAAADKTRPFGTLEKMEAADVSSDGLIDLLYKLKAKYRKNA VWVMNSNTAAKLQKLKNGNGDYIWRDRLVAGSPDTLLGRPVQYLETMPDAEAGKAFLAVGDFKRGYFI VDHTTGVRTRPDNITEPGFYKVHTDKYLGGGWDSNAIKVLELSGSGS*

[0570] SEQ ID NO: 3 EcCIEDL933 immature capsid protein

[0571] MPRI IELRQQKTAIKNQMRDMLENAEKENRSLNDAEGAKFDELRAKAESLDKDISRLEAIADEERSKP GKSSQTTDPAELRNYILTGETRALSTGVPADGGYTVIPELNTEIMRMLTDESTMRRICTVKKISSNEF KQLVSAGGATVNHGEEGKTREQTSTPQINEVSIKLYPVYAYPRTTQEIVDFSDVDILSWLTGEIGDTF TETEESDLWGDGDKKAKGFLSVPRAEKNDKERDFGTLQVIKPSESLAWTSADPLIDLKFALRKKYRK NAVWWNSTTAAKLQKVKNANGDYIWRDRLQAGDPDTLLGLPVEYLEFMPDNVIALGDFKRGYYIVDH ETGVRTRPDNLTEPGFIKIFTQKYLGGGWDSNAIKILELPQDDD*

[0572] SEQ ID NO: 4 HK022 capsid MSELALIQKAIEESQQKMTQLFDAQKAEIESTGQVSKQLQSDLMKVQEELTKSGTRLFDLEQKLASGA ENPGEKKSFSERAAEELIKSWDGKQGTFGAKTFNKSLGSDADSAGSLIQPMQIPGIIMPGLRRLTIRD LLAQGRTSSNALEYVREEVFTNNADWAEKALKPESDITFSKQTANVKTIAHWVQASRQVMDDAPMLQ SYINNRLMYGLALKEEGQLLNGDGTGDNLEGLNKVATAYDTSLNATGDTRADI IAHAIYQVTESEFSASGIVLNPRDWHNIALLKDNEGRYIFGGPQAFTSNIMWGLPWPTKAQAAGTFTVGGFDMASQVWDRMD ATVEVSREDRDNFVKNMLTILCEERLALAHYRPTAI IKGTFSSGS

[0573] SEQ ID NO: 5 HK106 capsid MSELALIQKAIEESQQKMTQLFDAQKAEIESTGQVSKQLQSDLMKVQEELTKSGTRLFDLEQKLASGA ENPGEKKSFSERAAEELIKSWDGKQGTFGAKTFNKSLGSDAGSAGSLIQPMQIPGIIMPGLRRLTIRD LLAQGRTSSNALEYVREEVFTNNADWAEKALKPESDITFSKQTANVKTIAHWVQASRQVMDDAPMLQ SYINNRLMYGLALKEEGQLLNGDGTGDNLEGLNKVATAYDTSLNATGDTRADI IAHAIYQVTESEFSA SGIVLNPRDWHNIALLKDNEGRYIFGGPQAFTSNIMWGLPWPTKAQAAGTFTVGGFDMASQVWDRMD ATVEVSREDRDNFVKNMLTILCEERLALAHYRPTAI IKGTFSAD

[0574] SEQ ID NO: 6 lambda phage capsid protein MSMYTTAQLLAANEQKFKFDPLFLRLFFRESYPFTTEKVYLSQIPGLVNMALYVSPIVSGEV RSRGGSTSEFTPGYVKPKHEVNPQMTLRRLPDEDPQNLADPAYRRRRI IMQNMRDEELAIAQVEEMQA VSAVLKGKYTMTGEAFDPVEVDMGRSEENNITQSGGTEWSKRDKSTYDPTDDIEAYALNASGWNI IV FDPKGWALFRSFKAVKEKLDTRRGSNSELETAVKDLGKAVSYKGMYGDVAIWYSGQYVENGVKKNFL PDNTMVLGNTQARGLRTYGC I QDADAQREG INAS ARYPKNWVTTGD PARE FTM I QS APLMLLAD PDE F VSVQLA

[0575] SEQ ID NO: 7 phage 80 capsid protein MSVYTTAQLLAVNEKKFKFDPLFLRIFFRETYPFSTEKVYLSQIPGLVNMALYVSPIVSGKVIRSRGG STSEFTPGYVKPKHEVNPLMTLRRLPDEDPQNLADPVYRRRRI ILQNMKDEELAIAQVEEKQAVSAVL SGKYTMTGEAFEPVEVDMGRSAGNNIVQAGAAAWSTRDKETYDPTDDIEAYALNASGWNI IVFDPKG WALFRSFKAVEKKLDTRRGSNSELETAVKDLGMAVSYKGMFGDVAIWYSGQYVENDVKKNYLPDLTM VLGNTQARGLRTYGCILDADAQREGINASTRYPKNWVQSGDPAREFTMIQSAPLMLLPDPDAFVSVKL A

[0576] SEQ ID NO: 8 KpCIDSM30104 adaptor protein MKAGKMKRRVTIQQFVSHQDPNTGSVTKEWRDVATVWGEIDSVSGRELVAAQAEQSEMTVRIWIRYRK GVTTKNRLTCTEKGMPVTIYDIKAVLPDADRTRLEIMCTGGLTSG*

[0577] SEQ ID NO: 9 EcCIGN02175 adaptor protein MRPGGLRQRVTIQNFTTSRTPSGGVIQEWYDVATVWAEVKGISGRELIAAGAEMSEVTFRMWIRYRSD VTSASRIIWKQKGHDAKAFDIQSAIPDEKATRLELLCKGGLKP*

[0578] SEQ ID NO: 10 EcCIEDL933 adaptor proteinMNIGRLRDRITIQTLKQTRAMTGEILETWEDGHTLWASVNMISSKEAISSGAELAIGTVRIWIRYRKD INATSRIKVSTGPLAGRVLNI IGQPLPDVARTRLEILCREGAEK*

[0579] SEQ ID NO: 11 HK106_adaptor MEPGRFRHRVKILTFTTSRDPSGQPVESWRGGRPISAEVKGISGREQMSGGVETAQATIRVWMRFRAD LNAS S RLE VLS GPYKGQVLN 11 GP PVANS TGTRLE I LCKTGAE K

[0580] SEQ ID NO: 12 HK022_adaptor MEPGRFRHRVKILTFTTSRDPSGQPVESWTGGNPVPAEVKRISGREQLSGGAETAQATIRVWMRATER VDKKVGKNSL

[0581] SEQ ID NO: 13 KpCIDSM30104 connector protein VAETIELAEAKLHCRIDGDDEDLLIQAYIDAALEVCQKHIGKRFDSGLELTPAIKIGCLMYVSQLYEY RTMISDVEAKEVPLAVSALWSVYRDVGVY*

[0582] SEQ ID NO: 14 EcCIGN02175 connector protein MSELIGLDEAKLHCRIDNDDSYEDAMIQAYIEASLEVCQKHIGKRFGAGLEFTPAIKIGCLMYVSQLY EYRTMI SDVEAKE I PLAI S ALWSVYRDVGVY*

[0583] SEQ ID NO: 15 EcCIEDL933 connector protein MTEELITLEEVKLHCRIDGDEEDQLISGYIAASLEACQIHIGRRFDDGLEFTPAIKIGCMMFIAHLYE NRQ I VADNAKTRVPMT I GALWTAYRDVGVY *

[0584] SEQ ID NO: 16 HK106_connector MAIDVLDVIPLSLFKQQIEFEEDDRDELITLYAQAAFDYCMRWCDEPAWKVAADIPAAVKGAVLLVFA DMFEHRTAQSEVQLYENAAAERMMFIHRNWRGKAESEEGS

[0585] SEQ ID NO: 17 HK022_connector MAIDVLDVISLSLFKQQIEFEEDDRDELITLYAQAAFDYCMRWCDEPAWKVAADIPAAVKGAVLLVFA DMFEHRTAQSEVQLYENAAAERMMFIHRNWRGKAESEEGS

[0586] SEQ ID NO: 18 lambda phage neck protein MADFDNLFDAAIARADETIRGYMGTSATITSGEQSGAVIRGVFDDPENISYAGQGVRVEGSSPSLFVR TDE VRQLRRGDTLT I GEENFWVDRVS PDDGGS CHLWLGRGVP PAVNRRR

[0587] SEQ ID NO: 19 phage 80 neck proteinMADFDNLFDESMARADTTIRGLMGAEARITSGSLSGVTLRGVFDDPENIGYAEVGIRIDGTRPTLFVN TSDVSGLERLDTLKVNGREFWVDRVGPDDCGSCHVWLGSGSPPGGSRRR

[0588] SEQ ID NO: 20 HK022 major tail protein MSVLTQGTQLFVLVKGKVSEVECITAFSPGSNPADQIEDTCLSERFDRSYKRGLRTPGTASLTLNADP KNTSHIMLYNLSISDDEEDQDLTFAIGWSDGTASPTAAENGASGAVDGLVLPDSRTWFVFKGYVSDFP FDFSANTWSTSAS IQRSGSAVWVPKWTP

[0589] SEQ ID NO: 21 HK106 major tail protein MSALYEKSQLTKILISSLPATKETMDSATFLDLSCTIKEIQFTGGQKQDIDVTTLCSTEQENINGLPS PSEISLSGNFYNNPAQDALRDAYDNDTTYGFQI IFPSGNGFKFLAEVRQHTWSSGTNGWAATFSLRL KGKPVPIDSVLKLTTDLPSSLSVAVGAAISMAWAAGGKPPYAYTWKKAGSTVSGQTSDTFNKATAVS GDAGDYTCWTDS S S PVKTVTS AACTLT I S

[0590] SEQ ID NO: 22 Ehh18_phi2 major tail (high possible donor) MSALYEKSQLTKILISSLPATKETMDSATFLDLSCTIKEIQFTGGQKQDIDVTTLCSTEQENINGLPS PSEISLSGNFYKNPAQDALREAYDNDTTYAFQVIFPSGKGFKFLAEIRQHTWSSGTNGWAATFSLRL KGKP

[0591] SEQ ID NO: 23 Ehh18_phi5 major tail (high possible donor) MSALYEKSQLTKILISSLPATKETMDSATFLDLSCTIKEIQFTGGQKQDIDVTTLCSTEQENINGLPS PSEISLSGNFYKNPAQDALREAYDNDTTYAFQVIFPSGKGFKFLAEIRQHTWSSGTNGWAATFSLRL KGKP

[0592] SEQ ID NO: 24 Ehh18_phi1 major tail (low possible donor) MTSKYEVTKGMTVAVSDAPVTAADFISSTFPGAGVTWLEAACATKEITFTGGQKGDIDVTTLCSTEQE QTNGLAAPAEMSITRNWVGDEEAQEALQTAYENDELRALRWFPSGNGFYVLVEVRQSSWSAATSSW GATYSLRVRGKPKRIFASGS

[0593] SEQ ID NO: 25 lambda phage major tail protein MPVPNPTMPVKGAGTTLWVYKGSGDPYANPLSDVDWSRLAKVKDLTPGELTAESYDDSYLDDEDADWT ATGQGQKSAGDTSFTLAWMPGEQGQQALLAWFNEGDTRAYKIRFPNGTVDVFRGWVSSIGKAVTAKEV ITRTVKVTNVGRPSMAEDRSTVTAATGMTVTPASTSWKGQSTTLTVAFQPEGVTDKSFRAVSADKTK ATVS VS GMT I TVNGVAAGKVN I PWS GNGE FAAVAE I TVTAS

[0594] SEQ ID NO: 26 phage 80 major tail proteinMPTPNPLAPVKGAGTTLWLYTGTGNAFANPLSDIDWNRLAKIKELTPGEMTAESYDDTYLDDEDADWN ATAQGAKSAGDTSFTLAWKPGEEGQKDLVAWFIDGSVRYYKIKYPNGTVDVFRGWCSSLGKAIPAKEV ITRTAKITNTGKPELAEESGSPNIPVTGVTLDKATASVAVGATTTLNVTVNPASASDKSFRVSSADRA KATVTANGNTLTVTGVAAGTAD I I VMTSDGNFVAVCKVTVTAA

[0595] SEQ ID NO: 27 HK022 tail tape measure protein MASKSLGTLTIDLIAKVGGFVSGLSQAERASQKWRKQVKEDAAAAAAAMTGFATAVGAAAIGAGVAGY NLLKTTSRQITESDRWAKSLNMSTQSLLAWQYAAEKAGVSGDQMADIFKDVGDKIGDAVLNKSGEAVG ALDALGLSAKKLAGESPDKQLLAISDALEKVKSNAEKTTILESLGNDLSKMLPLLDNGSEKLRQYMDA AKKFGVAPDDADIEKLVRVNALFEDMETQVNGVKIELAAGLASVDLSGLQKSIGDMGDVFKDPAVIQG LTDLVGGWDLATWLVRVGAE AGKL I DQYKGGS S VGLNAS I PE I ERRI KNLNADLDDKG I LAS FNR I G MDVSGKEAERAELQRRLAFLRNSQSTLPEIKLPEPVKTNYTLGAGETNGKPQKNTSGQKLDSAFKSAE RSYMRQIELIDTTGKKTAWTEQQKLQFDIADGKLQGLNETQKKRLASLAQEVDRLNAVKKANEENAK VAAFVANLQEQNENARADLGVDIHGAGLGDKQRERLRERLSIERSYLDQQRDLQKQYQSGDISQTVYD RETQALKDAQAERLGIQEDYYSQIDALQSDWVTGARDGLADWVDDSTNYATLAADAMKSALSGISSNI VDMLNGNKASWKDWGVSVLKIIEQVMVNMMIANAASSIGSLFGGAASSSASSGTAIQSYGASLQFNAK GGVYSSAD...

Claims

CLAIMS1. A chimeric infectious particle comprising:(a) a capsid from a first phage, phage satellite or phage-related element;and(b) a tail from a second phage, phage satellite or phage-related element;wherein the first and second phage, phage satellite or phage-related elements are different and / or the first and second phage, phage satellite or phage-related elements are not endogenous to the same bacterial species and / or strain.

2. A chimeric particle according to claim 1, wherein the first phage, phage satellite or phage-related element is selected from the group consisting of:(a) a phage satellite, optionally a capsid-forming PICI (cf-PICI), a phage inducible chromosomal islands (PICI), a P4-like satellite, ora PICI-like element (PLE); and (b) a phage from the order Caudovirales, optionally a phage from the family Podoviridae, Siphoviridae or Myoviridae.

3. A chimeric particle according to claim 1 or 2, wherein the first phage, phage satellite or phage-related element is:(a) a capsid-forming PICI (cf-PICI), optionally selected from the group consisting of KpCIDSM30104, EcCIGN02175, EcCIEDL, EcCISMS-3-5, EcCIPNUSAE044409, SeCIDerby, YaCI159, SfCI301, SfCI8401, EcCIIAI39, CfCICFNIH4, EcCIEC11-7286, EcCIEDIa, EcCIWW223, EpCIETW41, PgCIFDAARGOS.186, SdCICCFSAN010956, SeCIFDA336426-1, PmCIATCC29906, EcCIEO709, ECCIRM10386, KvCIGJ3, EcCICFSAN002236, EcCID8, EcCIRM10042, CpCITV06, EcCIHUST159, SeCI08-1209, EcCI392917, SeCIKentucky, GaCISCGC, GaCIWKBI, KpCIAR.0148, EcCIEDL933, EcCI144, EcCIPA40, SeCI7830, ECCIST130, KpCIKPNOI, EcCIPSUO103, KoCICAV175, XnCIATCC1906, EcCI315650, B..kocchi. BDGP4, B.cereus. BAG6X1-2, S.saprophyticus. CCUG38042, C.botulinum. B. Eklund.17B, S.pettenkoferi.589, S.haemolitycus. S167, S. equorum. DSM15097, S.aureus. VET0180R, S.xylosus. HKUOPL8, C.beijerinckii. WB53, S.arlettae.lOV5, S.. aureus. C0673,E.durans.4928STDY7071318, S.warneri. DE0454, L.rhammosus. GG, B.thuringiensis. BGSC.4W1.4W1, L.casei. Lc705, C.sporogenes.87-0535, S.hominis. SNUC.5746, L.casei. BL23;(b) a PICI, optionally selected from the group consisting of EcCI11368.1, EcCIIHE3034, ECCIRM13514, EcCIRM 12579, EcCIATCC_25922, EcCI042, PcCIPCC221, EcCIDi14, SbCISb277, PmCIOH1905, PhaCIATCC43949, EcCICFT073, EcCI11128, SAPI1, LICIKF147, LICIA76-1, SaPlmw2, SAPI2, SpnCITaiwan-0.2, SpnCITaiwan- 0.03, SpnCI-A45-1.9, SaPIbovI, LICISK11, SpnCITCH8341-0.25, SpnCIINV104- 1.06, EfCIV583, MG1363-1 and LICI-CV56-1;(c) a PICI-like element (PLE), optionally selected from the group consisting of PLE1, PLE2, PLE3, PLE4 and PLE5;(d) a P4-like satellite, optionally selected from the group consisting of P4-like satellites from any of Lelliottia amnigena, Escherichia coli, Shigella boydii, Klebsiella pneumoniae, Salmonella enterica, Klebsiella variicola, Klebsiella sp., Shimwellia blattae, Escherichia albertii, Enterobacter cloacae, Enterobacter hormaechei, Citrobacter freundii, Cronobacter malonaticus, Escherichia fergusonii, Buttiauxella sp., Enterobacteriaceae bacterium, Citrobacter werkmanii, Kluyvera intermedia, Escherichia marmotae, Enterobacter sp., Cedecea lapagei, Klebsiella oxytoca, Raoultella ornithinolytica, Cronobacter muytjensii, Salmonella sp., Kosakonia cowanii, Enterobacter roggenkampii, Kosakonia sp., Metakosakonia sp., Citrobacter sp., Klebsiella quasipneumoniae, Citrobacter portucalensis, Klebsiella michiganensis, Klebsiella aerogenes, Kosakonia sacchari, Cronobacter sakazakii, Enterobacter kobei, Raoultella planticola, Atlantibacter hermannii, Pantoea vagans, Pantoea alhagi, Mixta calida, Erwinia billingiae, Pantoea sp., Erwinia sp., Pantoea rwandensis, Pantoea ananatis, Tatumella ptyseos, Edwardsiella sp., Edwardsiella piscicida, Edwardsiella tarda, Edwardsiella anguillarum, Hafnia sp., Hafnia alvei, Pectobacterium wasabiae, Pectobacterium carotovorum, Pectobacterium atrosepticum, Pectobacterium polaris, Pectobacterium parmentieri, Serratia sp., Serratia marcescens, Yersinia enterocolitica, Yersinia aldovae, Yersinia ruckeri, Serratia fonticola, Serratia plymuthica, Yersinia sp., Yersinia massiliensis, Serratia liquefaciens, Yersinia frederiksenii, Serratia nematodiphila or Yersinia similis- (e) a Siphoviridae phage, optionally selected from the group consisting of E. coll phages lambda, 80, HK97, HK106, HK022, T1, and T5; Staphylococcus aureus phages φ11 and 80 α, Salmonella enterica BTP1; and Lactococcus lactis TP901-1;(f) a Myoviridae phage, optionally selected from the group consisting of E. coli phages T4, P1, P2, Mu, T2; Bacillus subtilis SPO1; Staphylococcus aureus phages φK, φ812, φMR11;(g) a Podoviridae phage, optionally selected from the group consisting of E. coll phage T7; Salmonella enterica P22; Bacillus subtilis phi29; Streptococcus pneumoniae CP- 1; Staphylococcus aureus φ44RR2.8t; or(h) a phage selected from the group consisting of E. coll phages M13, MS2, PhiX174, Pseudomonas syringae phage φ6, Vibrio cholerae phage Autolykivirus, Acinetobacter baumannii phage φAb1, PRD1 phage, and cyanophage.

4. A chimeric particle according to claim 3, wherein the first phage, phage satellite or phage-related element is a capsid-forming PICI (cf-PICI) selected from the group consisting of KpCIDSM30104, EcCIGN02175.

5. A chimeric particle according to claim 3 or 4, wherein the capsid comprises a plurality of mature capsid proteins each comprising or consisting of an amino acid sequence comprising or consisting of at least 60% sequence identity to any one of SEQ ID NOs: 1 to 7, optionally any one of SEQ ID NOs: 1 to 3; preferably each mature capsid proteins comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 1 to 7, optionally any one of SEQ ID NOs: 1 to 3.

6. A chimeric particle according to any one of the preceding claims, wherein the second phage, phage satellite or phage-related element is a phage.

7. A chimeric particle according to claim 6, wherein the phage selected from the group consisting of:(a) a Siphoviridae phage, optionally selected from the group consisting of E. coli phages lambda, 80, HK97, HK106, HK022, T1, and T5; Staphylococcus aureus phages φ11 and 80 α, Salmonella enterica BTP1; and Lactococcus lactis TP901-1;(b) a Myoviridae phage, optionally selected from the group consisting of E. coli phages T4, P1, P2, Mu, T2; Bacillus subtilis SPO1; Staphylococcus aureus phages φK, φ812, φMR11;(c) a Podoviridae phage, optionally selected from the group consisting of E. coll phage T7; Salmonella enterica P22; Bacillus subtilis phi29; Streptococcus pneumoniae CP- 1; Staphylococcus aureus φ44RR2.8t; or(d) a phage selected from the group consisting of E. coli phages M13, MS2, PhiX174, Pseudomonas syringae phage φ6, Vibrio cholerae phage Autolykivirus, Acinetobacter baumannii phage φAb1, PRD1 phage, and cyanophage;wherein optionally the chimeric particle comprises a tail comprising or consisting of a major tail protein which has an amino acid sequence comprising or consisting of at least 60% sequence identity to any one of SEQ ID NOs: 20 to 26, particularly a major tail protein which has an amino acid sequence of any one of SEQ ID NOs: 20 to 26.

8. A chimeric particle according to any one of the preceding claims, wherein:(a) the capsid further comprises a neck which is configured to connect the capsid from the first phage, phage satellite or phage-related element with the tail from the second phage, phage satellite or phage-related element; and / or(b) the tail comprises an amino acid sequence which is configured to connect to the capsid from the first phage, phage satellite or phage-related element, preferably which is configured to connect to the neck of the capsid from the first phage, phage satellite or phage-related element.

9. A chimeric particle according to claim 8, wherein the neck comprises:(a) a capsid-tail adaptor polypeptide which comprises or consists of an amino acid sequence comprising or consisting of at least 60% sequence identity to any one of SEQ ID NOs: 8 to 12, particularly any one of SEQ ID NOs: 8 to 10;(b) a capsid-tail connector polypeptide which comprises or consists of an amino acid sequence comprising or consisting of has at least 60% sequence identity to any one of SEQ ID NOs: 13 to 17, particularly any one of SEQ ID NOs: 13 to 15; and / or(c) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of has at least 60% sequence identity to any one of SEQ ID NOs: 35 to 37,;wherein optionally the neck comprises:(i) a capsid-tail adaptor polypeptide which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 8 to 12, particularly any one of SEQ ID NOs: 8 to 10;(ii) a capsid-tail connector polypeptide which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 13 to 17, particularly any one of SEQ ID NOs: 13 to 15; and / or(iii) a portal protein which comprises or consists of an amino acid sequence comprising or consisting of any one of SEQ ID NOs: 35 to 37.

10. A chimeric particle according to any one of the preceding claims, wherein the capsid is capable of interacting with:(a) a tail from a single second phage, phage satellite or phage-related element; or (b) a tail from two or more different second infectious phage, phage satellites or phage- related elements.

11. A chimeric particle according to any one of the preceding claims, which is capable of infecting:(a) a single bacterial species or strain thereof;(b) two or more different bacterial species; and / or(c) two or more strains of a single bacterial species.

12. Achimeric particle according to any one of the preceding claims, which further comprises a nucleic acid molecule, optionally wherein:(a) said nucleic acid molecule is DNA or RNA; and / or(b) the nucleic acid molecule is an exogenous nucleic acid molecule compared with the nucleic acid molecule of the first phage, phage satellite or phage-related element and / or the nucleic acid molecule of the second phage, phage satellite or phage- related element, preferably wherein the nucleic acid molecule is an exogenous nucleic acid molecule compared with the nucleic acid molecules of both the first and second phage, phage satellite or phage-related element.

13. Achimeric particle according to claim 12, wherein the nucleic acid molecule:(a) encodes a protein capable of killing one or more target bacteria, optionally:(i) an antibiotic and / or a protein which reduces antibiotic resistance; or(ii) a lytic enzyme;(b) encodes a reporter protein, e.g. a fluorescent protein or an enzymatic marker;(c) encodes a protein which alters the physiology of the target bacteria; and / or(d) modifies the genome of one or more target bacteria.

14. A chimeric particle according to any of the preceding claims, wherein the first phage, phage satellite or phage related element is a phage and the second phage, phage satellite or phage related element is a phage.

15. A panel comprising two or more chimeric particles as defined in any one of claims 1 to 14, wherein the two or more chimeric particles target the same or different bacterial species and / or strains, optionally wherein each of the two or more chimeric particles target at least one different bacterial species and / or strain.

16. A panel according to claim 15, wherein the two or more chimeric particles comprise:(a) the same capsid and different tails;(b) different capsids and the same tails; or(c) different capsids and different tails.

17. A composition comprising or consisting of:(a) a capsid from a first phage, phage satellite or phage-related element; and(b) a tail from a second phage, phage satellite or phage-related element;wherein the first and second phage, phage satellite or phage-related element are different, wherein the capsid and the tail are capable of assembling to form a chimeric infectious particle as defined in any one of claims 1 to 14.

18. A composition according to claim 17, which comprises:(a) two or more different capsids; and / or(b) two or more different tails.

19. A pharmaceutical formulation comprising chimeric particle as defined in any one of claims 1 to 14, a panel as defined in claim 15 or 16, or a composition as defined in claim 17 or 18, and at least one pharmaceutically acceptable carrier.

20. A kit of parts comprising or consisting of:(a) a first composition comprising or consisting of a capsid from a first phage, phage satellite or phage-related element; and(b) a second composition comprising or consisting of a tail from a second phage, phage satellite or phage-related element;wherein:the first and second pharmaceutical compositions are stored in separate containers; and the first and second phage, phage satellite or phage-related element are different, wherein the capsid and the tail are capable of assembling to form a chimeric infectious particle as defined in any one of claims 1 to 14;optionally wherein said kit comprises two or more first compositions each comprising a different capsid and / or two or more second compositions each comprising a different tail;and further optionally wherein the kit of parts further comprises instructions for use.

21. A tail-less capsid from a phage, phage satellite or phage-related element, which comprises a nucleic acid molecule.

22. A tail-less capsid according to claim 21, wherein:(a) the phage, phage satellite or phage-related element is as defined in any one of claims 2 to 5;(b) the capsid further comprises a neck which is configured to connect the capsid from the first phage, phage satellite or phage-related element with the tail from the second phage, phage satellite or phage-related element, wherein optionally said neck is as defined in claim 9; and / or(c) the capsid is capable of interacting with (i) a tail from a single second phage, phage satellite or phage-related element or (ii) a tail from two or more different second infectious phage, phage satellites or phage-related elements;(d) the nucleic acid molecule is as defined in claim 12 or 13;(e) the tail-less capsid is non-enveloped; and / or(f) the tail-less capsid is in isolated form.

23. A panel of tail-less capsids as defined in claim 21 or 22, which comprises two or more different tail-less capsids.

24. An isolated tail from a phage, phage satellite or phage-related element, wherein the tail is capable of assembling with a tail-less capsid as defined in claims 21 or 22 to form a chimeric infectious particle as defined in any one of claims 1 to 14.

25. An isolated tail according to claim 24, wherein(a) the phage, phage satellite or phage-related element is as defined in any one of claims 2 to 5;(b) the isolated tail from a second phage, phage satellite or phage-related element is capable of assembling with the tail-less capsid of a first phage, phage satellite or phage-related element capsid via a neck comprised in the tail-less capsid, wherein optionally said neck is as defined in claim 9; and / or(c) the isolated tail is capable of interacting with (i) a tail-less capsid from a single first phage, phage satellite or phage-related element or (ii) a tail-less capsid from two or more different first phage, phage satellites or phage-related elements.

26. A panel of isolated tails as defined in claim 24 or 25, which comprises two or more different isolated tails.

27. A kit of parts comprising or consisting of:(a) a first composition comprising or consisting of a tail-less capsid from a first phage, phage satellite or phage-related element as defined in claim 21 or 22, or a panel of tail-less capsids as defined in claim 23; and(b) a second composition comprising or consisting of an isolated tail from a second phage, phage satellite or phage-related element as defined in claim 24 or 25, or a panel of isolated tails as defined in claim 26;wherein optionally:the first and second pharmaceutical compositions are stored in separate containers; andthe first and second phage, phage satellite or phage-related element are different, wherein the tail-less capsid and the isolated tail are capable of assembling to form a chimeric infectious particle as defined in any one of claims 1 to 14;further optionally wherein the kit of parts further comprises instructions for use.

28. A nucleic acid comprising or consisting of:(a) a nucleotide sequence encoding a capsid from a first phage, phage satellite or phage- related element; and / or(b) a nucleotide sequence encoding a tail from a second phage, phage satellite or phage- related element;wherein the first and second phage, phage satellite or phage-related element are different, wherein the capsid and the tail are capable of assembling to form a chimeric infectious particle as defined in any one of claims 1 to 14;and wherein optionally:the nucleotide sequence encoding the capsid and / or the nucleotide sequence encoding the tail are operably linked to a promoter; orthe nucleotide sequence encoding the capsid and / or the nucleotide sequence encoding the tail are in a polycistronic cassette;and wherein further optionally said nucleic acid further comprises a nucleic acid sequence which will be contained within the capsid of the chimeric particle.

29. An expression vector comprising a nucleic acid as defined in claim 28.

30. A bacterial cell comprising a nucleic acid as defined in claim 28 or an expression vector as defined in claim 29, which bacterial cell optionally comprises:(a) a single nucleic acid or expression vector encoding the capsid;(b) a single nucleic acid or expression vector encoding the tail;(c) a single nucleic acid or expression vector encoding the capsid and the tail; or (d) a first nucleic acid or expression vector encoding the capsid and a second nucleic acid or expression vector encoding the tail;and wherein further optionally said nucleic acid or expression vector further comprises a nucleic acid sequence which will be contained within the capsid of the chimeric particle.

31. A method of producing a chimeric infectious particle as defined in any one of claims 1 to 14, said method comprising:(a) culturing a bacterial cell as defined in claim 30 under conditions for production of a chimeric infectious particle, wherein optionally said method further comprises purifying the resulting chimeric particle; or(b) (i) culturing a first bacterial cell as defined in claim 30 to produce the capsid under conditions for production of the capsid;(ii) culturing a second bacterial cell as defined in claim 30 to produce the tail under conditions for production of the tail; and(iii) combining the capsid produced in step (i) with the tail produced in step (i) to form a chimeric particle;wherein optionally said method further comprises purifying the capsid, tail and / or chimeric particle.

32. A method of producing a chimeric infectious particle, said method comprising contacting an isolated capsid from a first phage, phage satellite or phage-related element, with an isolated tail from a second phage, phage satellite or phage-related element in conditions that allow for the assembly of the capsid and the tail to result in a chimeric infectious particle, wherein:the first and second phage, phage satellite or phage-related elements are different, and optionally:said method further comprises purifying and / or isolating the resulting chimeric infectious particle;said capsid is a tail-less capsid as defined in any one of claims 21 or 22;said isolated tail is as defined in any one of claims 24 or 25; and / orsaid chimeric infectious particle is as defined in any one of claims 1 to 14.

33. A chimeric infectious particle, obtainable by the method according to claim 31 or 32, wherein optionally said chimeric infectious particle is as defined in any one of claims 1 to 14.

34. A pharmaceutical formulation comprising a bacterial cell according to claim 30 and at least one pharmaceutically acceptable carrier.

35. A chimeric infectious particle as defined in any one of claims 1 to 14, a panel as defined in claim 15 or 16, a nucleic acid as defined in claim 28, an expression vector as defined in claim 29, a bacterial cell as defined in claim 30, a composition as defined in claim 17 or 18, or a pharmaceutical formulation as defined in claim 19 or 34 for use in a method of therapy.

36. A chimeric infectious particle, panel, nucleic acid, expression, bacterial cell or pharmaceutical formulation for use according to claim 35, wherein the therapy is for treating a subject, preferably a mammalian subject, more preferably a human subject.

37. A chimeric infectious particle, panel, nucleic acid, expression, bacterial cell or pharmaceutical formulation for use according to claim 35 or 36, wherein the therapy is for:(a) treating and / or preventing a bacterial infection; and / or(b) modulating the gut microbiome to improve digestion and / or immunity.

38. A chimeric infectious particle, panel, nucleic acid, expression, bacterial cell or pharmaceutical formulation for use according to claim 35, wherein the bacterial infection is selected from respiratory infections, urinary tract infections, skin and soft tissue infections, bloodstream infections (sepsis), gastrointestinal infections, bone and joint infections (osteomyelitis, septic arthritis), meningitis, endocarditis, wound infections, peritonitis, otitis media, sinusitis, dental infections (abscesses), pelvic inflammatory disease, eye infections (conjunctivitis, keratitis), infections that are generated by Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis, Pseudomonas aeruginosa, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, Clostridium difficile, Shigella spp., Vibrio cholerae, Kingella kingae, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus viridans, Enterococcus faecalis, Bacteroides fragilis, Moraxellacatarrhalis, Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Chlamydia trachomatis or other relevant pathogens and / or multiple drug resistant bacterial infection.

39. Use of a chimeric infectious particle as defined in any one of claims 1 to 14, a panel as defined in claim 15 or 16, a nucleic acid as defined in claim 28, an expression vector as defined in claim 29, a bacterial cell as defined in claim 30, a composition as defined in claim 17 or 18, ora pharmaceutical formulation as defined in claim 19 or 34 for:(a) drug discovery, such as discovery of antimicrobial agents;(b) antibacterial treatment of agricultural products such as foodstuffs and animal feed; (c) decontamination of contaminated environments, optionally clinical environments, food-processing environments or water distribution systems;(d) degradation and / or prevention of biofilms;(e) controlling plant disease;(f) improving plant yield;(g) disinfecting water sources;(h) research;(i) biodefence; and / or(j) nanotechnology, such as nanomaterial templates or developing drug delivery systems.

40. A method of diagnosing infection with a bacterial species and / or bacterial strain of interest, said method comprising:(a) contacting a sample obtained from a subject with a chimeric infectious particle as defined in any one of claims 1 to 14, a panel as defined in claim 15 or 16, a nucleic acid as defined in claim 28, an expression vector as defined in claim 29, a bacterial cell as defined in claim 30, a composition as defined in claim 17 or 18, or a pharmaceutical formulation as defined in claim 19 or 34, wherein the chimeric particle comprises a nucleic acid molecule comprising a reporter gene or encoding a reporter protein; and(b) detecting the reporter gene or protein;wherein a positive signal for the reporter gene or protein indicates the presence of an infection by a bacterial species and / or strain which is susceptible to infection by the chimeric particle;wherein optionally two or more different chimeric particles capable of infecting different bacterial species and / or strains are used, said two or more different chimeric particles each comprising a nucleic acid molecule comprising a different reporter gene or encoding a different reporter protein, such that the different bacterial species and / or strains can be differentiated based on the reporter gene or protein detected.

41. A method of treatment comprising the step of:(a) identifying the pathologic bacterial species and / or strains present in a subject; and (b) providing to the subject a therapeutically effective amount of chimeric infectious particle as defined in any one of claims 1 to 14, a panel as defined in claim 15 or 16, a nucleic acid as defined in claim 28, an expression vector as defined in claim 29, a bacterial cell as defined in claim 30, a composition as defined in claim 17 or 18, or a pharmaceutical formulation as defined in claim 19 or 34 which target the identified pathologic bacterial species and / or strains present in the subject;wherein optionally said method of treatment comprises identifying the pathologic bacterial species and / or strains present in the subject by a method of claim 40.

42. A tail-less capsid as defined in claim 21 or 22, or a panel of tail-less capsids as defined in claim 23, andan isolated tail as defined in claim 24 or 25, or a panel of isolated tails as defined in claim 26,for use in a method of therapy.

43. The tail-less capsid or panel of tail-less capsids, and the isolated tail, or panel of isolated tails for use according to claim 42, wherein the method of therapy is for treating a subject, preferably a mammalian subject, more preferably a human subject.

44. The tail-less capsid or panel of tail-less capsids, and the isolated tail, or panel of isolated tails for use according to claim 42 or 43, wherein the method of therapy comprises the step of:(a) administering a therapeutically effective amount of an isolated tail as defined in claim 24 or 25, or a panel of isolated tails as defined in claim 26 to the subject in need thereof; and(b) subsequently administering a therapeutically effective amount of a tail-less capsid as defined in claim 21 or 22, ora panel of tail-less capsids as defined in claim 23 to the subject in need thereof.

45. The tail-less capsid or panel of tail-less capsids, and the isolated tail, or panel of isolated tails for use according to claim 44, wherein step (b) is performed no more than about 24h after step (a), no more than about 12h after step (a), no more than about 8h after step (a), no more than about 4h after step (a), no more than about 2h after step (a) or no more than about 1h after step (a).

46. The tail-less capsid or panel of tail-less capsids, and the isolated tail, or panel of isolated tails for use according to any one of claims 42 to 45, wherein the therapy is for:(a) treating and / or preventing a bacterial infection; and / or(b) modulating the gut microbiome to improve digestion and / or immunity.

47. The tail-less capsid or panel of tail-less capsids, and the isolated tail, or panel of isolated tails for use according to claim 46, wherein the bacterial infection is selected from respiratory infections, urinary tract infections, skin and soft tissue infections, bloodstream infections (sepsis), gastrointestinal infections, bone and joint infections (osteomyelitis, septic arthritis), meningitis, endocarditis, wound infections, peritonitis, otitis media, sinusitis, dental infections (abscesses), pelvic inflammatory disease, eye infections (conjunctivitis, keratitis), infections that are generated by Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis, Pseudomonas aeruginosa, Clostridium perfringens, Salmonella spp., Campylobacter jejuni, Clostridium difficile, Shigella spp., Vibrio cholerae, Kingella kingae, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus viridans, Enterococcus faecalis, Bacteroides fragilis, Moraxella catarrhalis, Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Chlamydia trachomatis or other relevant pathogens and / or multiple drug resistant bacterial infection.

48. A method of diagnosing infection with a bacterial species and / or bacterial strain of interest, said method comprising:(a) contacting a sample obtained from a subject with an isolated tail as defined in claim 24 or 25, or a panel of isolated tails as defined in claim 26;(b) contacting the sample obtained from the subject with a tail-less capsid as defined in claim 21 or 22, or a panel of tail-less capsids as defined in claim 23; wherein the tailless capsid or panel of tail-less capsids comprises a nucleic acid molecule comprising a reporter gene or encoding a reporter protein; and(c) detecting the reporter gene or protein;wherein a positive signal for the reporter gene or protein indicates the presence of an infection by a bacterial species and / or strain which is susceptible to recognition by the isolated tail or panel of isolated tails;wherein optionally the sample is washed at least one, at least twice or at least three times, between steps (a) and (b).

49. A method of treatment comprising the step of:(a) identifying the pathologic bacterial species and / or strains present in a subject; and (b) providing to the subject a therapeutically effective amount of an isolated tail as defined in claim 24 or 25, or a panel of isolated tails as defined in claim 26 which target the identified pathologic bacterial species and / or strains present in the subject; and(c) subsequently providing to the subject a therapeutically effective amount of a tail-less capsid as defined in claim 21 or 22, or a panel of tail-less capsids as described in claim 23;wherein optionally said method of treatment comprises identifying the pathologic bacterial species and / or strains present in the subject by a method of claim 48.

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