Therapeutic Uses of Pleuromutilin

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof for use specifically in the treatment or prevention of bacterial infections mediated by F. tularensis. [Formula 1] JPEG2025529559000009.jpg40169 where n is 0 to 4; m is 0 or 1, provided that the sulfur atom and R3 are in adjacent positions (when m = 0, R3 is in the 2' position, and when m = 1, R3 is in the 1' position); R is ethyl or vinyl; R1 is hydrogen or (C 1-6 ) alkyl, R2 is hydrogen or -(C 3-6 ) cycloalkyl, -unsubstituted (C 1-6 ) alkyl, or - one or more -two hydroxy; preferably one or two -methoxy, halogens, and -(C 3-6 ) cycloalkyl, (C 1-6 ) alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring containing at least one nitrogen atom or one nitrogen and one additional heteroatom (e.g., selected from N or O), or R1 is hydroxy and R2 is formyl; R3 is OH, OR4, a halogen atom, or R3 is bonded to 2' and p is 2 or 3; -O-(CH2) p represents -O-; R4 is an unsubstituted (C 1-6 ) alkyl or (C 3-6 ) cycloalkyl.

Description

Detailed Description of the Invention

[0001] The present invention relates to novel therapeutic uses of pleuromutilins.

[0002] Pleuromutilin, a compound of formula (A)

[0003] [ka]

[0004] is a naturally occurring antibiotic produced, for example, by the basidiomycetes Pleurotus mutilus and P. passeckerianus. See, for example, The Merck Index, 12th edition, item 7694.

[0005] Numerous additional pleuromutilins that have the main ring structure of pleuromutilin and in which the primary hydroxy group is substituted have been developed, for example, as antibacterial agents. Due to their pronounced antibacterial activity, a group of pleuromutilin derivatives, the amino-hydroxy-substituted cyclohexylsulfanylacetylmutilins, as disclosed in WO 2008 / 113089, have attracted particular interest. As described in WO 2008 / 113089, 14-O-{[(4-amino-2-hydroxycyclohexyl)sulfanyl]-acetyl}-mutilin is a particularly useful compound because it exhibits activity against both gram-positive and gram-negative bacteria.

[0006] Pharmaceutically active compounds (semisynthetic compounds) derived from pleuromutilins are ribosomal protein synthesis inhibitors. Representative semisynthetic pleuromutilins for human use include retapamulin (compound of formula (B), approved as AltargoP® or AltabaxP®), a topical agent approved for the short-term treatment of rash and infected small lacerations, abrasions, or sutured wounds, and lefamulin (compound of formula (VII), approved as Xenleta®) for the treatment of community-acquired bacterial pneumonia (CABP) in adults. Valnemulin (compound of formula (C), approved as Econor®) and tiamulin (compound of formula (D), approved as Denagard®) are two other semisynthetic pleuromutilin derivatives that have been used systemically as antibiotics in veterinary medicine for many years.

[0007] [ka]

[0008] Approved semi-synthetic compounds derived from pleuromutilins have shown excellent activity against bacterial organisms, including Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus (including MRSA), Moraxella catarrhalis, Legionella pneumophila, Chlamydophila pneumoniae, and Mycoplasma pneumoniae, among others.

[0009] Tularemia is an infectious disease caused by the bacterium Francisella tularensis (F. tularensis). Such infections in humans are zoonotic, meaning the pathogen circulates in wild animals and is transmitted, for example, by parasites. The frequency of F. tularensis infection in humans is fairly low (rare disease), and outbreaks are characterized by localized outbreaks. Tularemia can result from aerosolized F. tularensis, and this bacterium is highly contagious. Therefore, the causative agent, Francisella tularensis, is considered a viable biological warfare agent, i.e., a biothreat.

[0010] WO2007 / 062333, WO2007 / 062334 and WO2007 / 062335 refer to certain pleuromutilin compounds with O-acyl-carbamate linkers and mention the activity of the individual compounds against several species of bacteria, including F. tularensis. However, the applications do not disclose microbiological data, such as minimum inhibitory concentrations (MICs).

[0011] Summary of the Invention Surprisingly, it has now been found that the pleuromutilin derivatives disclosed in WO2008 / 113089A1 exhibit antibacterial activity against the biothreat bacterium F. tularensis. The pleuromutilin derivatives, in particular lefamulin, exhibit in vitro and in vivo activity against bacterial strains known to cause tularemia in humans.

[0012] Thus, in a first aspect, the present invention relates to a compound as defined in claims 1 to 6, in particular lefamulin, or a pharmaceutically acceptable salt, solvate, prodrug or ester of a metabolite thereof, for use specifically in the treatment or prevention of bacterial infections mediated by F. tularensis.

[0013] In a further aspect, the present invention relates to a method for the treatment or prevention of bacterial infections mediated by F. tularensis, comprising administering to a subject in need of such treatment a compound as defined in claims 1 to 6 (in particular lefamulin) or a pharmaceutically acceptable salt, solvate, prodrug or ester of a metabolite thereof.

[0014] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the results of an in vivo study of mice challenged with an aerosol of F. tularensis subsp. tularensis SchuS4 at different oral doses of lefamulin (Lef), showing survival probability over time compared to untreated controls and ciprofloxacin (Cipro) treatment.

[0015] Detailed Description of the Invention Lefamulin is a compound of general formula (I), more particularly, lefamulin is a compound of formula (VII):

[0016] [ka]

[0017] That is, 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin (also known as "BC-3781").

[0018] Hereinafter, the term "lefamulin," as normally used without further explanation, is intended to encompass both the free base form of lefamulin and its salts and solvates.

[0019] Lefamulin was developed for systemic use to treat serious bacterial infections in humans and was approved for medical use in the United States in 2019 to treat community-acquired bacterial pneumonia (CABP) in adults.

[0020] The compounds used according to the present invention have been found to have antibacterial activity against F. tularensis. As shown in Example 1, lefamulin exhibits potent inhibition against a variety of different subspecies of F. tularensis. In vitro activity translates to in vivo activity, as oral treatment with lefamulin was shown to be effective in extending survival after aerosol challenge with the highly virulent F. tularensis subsp. tularensis SchuS4 strain (Example 2).

[0021] The present invention therefore relates to a compound as defined in claims 1 to 6, in particular lefamulin, for use in the treatment or prevention of bacterial infections mediated by F. tularensis, the use of said compound in the treatment or prevention of bacterial infections mediated by F. tularensis and / or the use of said compound in the manufacture of a medicament for the treatment or prevention of bacterial infections mediated by F. tularensis.

[0022] Francisella tularensis is a Gram-negative, facultative intracellular bacterium that can survive and grow within eukaryotic cells, including macrophages. Francisella tularensis currently consists of four subspecies (abbreviated as subsp. or ssp.): -tularensis (type A or serotype A), -holarctica (type B or serotype B), -novicida, and -mediasiatica, It is classified as follows.

[0023] Type A strains are more virulent, occur only in North America and Mexico, and cause the most severe form of human disease. Type B is found throughout the Northern Hemisphere and is less pathogenic in humans than type A and F. tularensis subsp. mediasiatica, which is found in Central Asia (Champion MD et al., PLoS Pathog. 2009, 5(5): e1000459, DOI: 10.1371 / journal.ppat.1000459). There is ongoing debate as to whether subspecies F. novicida represents a fourth subspecies of F. tularensis or a separate species, and due to its aquatic reservoir and very low pathogenicity in humans, it is sometimes classified as a separate species, "F. novicida" (Kingry LC, Petersen JM, Front Cell Infect Microbiol 2014, 4:35, DOI: 10.3389 / fcimb.2014.00035; Caspar Y, Maurin M, Front Cell Infect Microbiol 2017, 7:122 DOI: 10.3389 / fcimb.2017.00122).

[0024] In one embodiment, the bacterial infection is mediated by a subspecies of F. tularensis selected from the group consisting of F. tularensis subsp. tularensis (type A), F. tularensis subsp. holarctica (type B), F. tularensis subsp. mediasiatica and F. tularensis subsp. novicida, preferably by a subspecies of F. tularensis selected from the group consisting of F. tularensis subsp. tularensis (type A), F. tularensis subsp. holarctica (type B), and F. tularensis subsp. novicida.

[0025] Tularemia is the general term for an infectious disease, a bacterial infection transmitted by F. tularensis. Depending on the subject or zoonotic origin, non-medical synonyms of tularemia, such as rabbit fever or deer fly fever, are used.

[0026] In one embodiment, the bacterial infection mediated by F. tularensis is tularemia.

[0027] In one embodiment, the compound is administered (or adapted to be administered) to a human.

[0028] Treating, treatment or to treat as understood herein includes, on the one hand, curing, curation or to cure completely so that a condition (bacterial infection) is terminated, and, on the other hand, also includes ameliorating, amelioration or to ameliorate so that such a condition is at least partially or individually alleviated.

[0029] The treatment typically involves administering a compound used according to the present invention to a subject in need thereof, such as, in one embodiment, a subject diagnosed with a bacterial infection mediated by F. tularensis. The subject may have a medical history that includes early symptoms of bacterial infection, resulting in an early diagnosis of the bacterial infection and later onset of current symptoms. Thus, in a preferred embodiment, the compound for use according to the present invention is administered to a subject exhibiting symptoms of or diagnosed with a bacterial infection mediated by F. tularensis. However, the present invention is useful in the context of both therapeutic and prophylactic treatment.

[0030] Preventing, prevention, or to prevent includes administering a compound before a condition is diagnosed or before the full set of (all) disease symptoms of a condition are manifested. The term prevention is synonymous with prophylaxis.

[0031] For example, prophylaxis according to the present invention is contemplated if a subject is infected with F. tularensis but does not exhibit symptoms of the bacterial infection (asymptomatic carrier), or if the subject has been exposed to and / or is susceptible to exposure to the bacteria.

[0032] Thus, in one embodiment, the compounds are used for post-exposure prophylaxis (PEP).

[0033] Suitable dosages of the compounds administered according to the present invention, particularly lefamulin, will, of course, vary depending upon, for example, the individual host, the mode of administration, and the nature and severity of the condition being treated. However, typically, daily dosages required to obtain satisfactory results in larger mammals, e.g., humans, will be in the range of about 0.5 mg to 3 g of the compounds used according to the present invention, conveniently administered in divided doses up to four times daily.

[0034] The compound used according to the present invention can be administered by any conventional route, for example, enteral administration including nasal, buccal, rectal, oral administration; parenteral administration including intravenous, intramuscular, subcutaneous, transdermal administration; or topical administration, for example, pulmonary, transdermal, intranasal, intratracheal, intradermal administration, for example, in the form of coated or uncoated tablets, capsules, injection solutions or suspensions, for example, in the form of ampoules, vials, ointments, creams, gels, pastes, inhalation powders, effervescents, tinctures, lipsticks, drops, sprays, patches, or suppositories.In particular, the route and form of administration can be selected from the same methods as those of antibiotics, for example, tetracyclines (for example, doxycycline, tetracycline), aminoglycosides (for example, streptomycin, gentamicin), fluoroquinolones (for example, ciprofloxacin) or chloramphenicol.

[0035] Preferably, the compounds used in accordance with the present invention are administered intravenously (IV) or orally.

[0036] In particular, oral treatment options would be beneficial for widespread use in populations, for example, when post-exposure prophylaxis is required, and in vivo data demonstrate the efficacy of orally applied lefamulin.

[0037] A preferred pharmaceutical composition of lefamulin for injection is disclosed in WO 2016 / 202788 A1, the contents of which are incorporated herein by reference.

[0038] The compounds used according to the invention, in particular lefamulin, can be administered in the form of a pharmaceutically acceptable salt, for example an acid addition salt, or in free form, optionally in the form of a solvate.

[0039] In one embodiment, the compound is in the form of a salt and / or solvate.

[0040] Salts of the compounds used according to the present invention include acid addition salts. Pharmaceutically acceptable acid addition salts include salts of the compounds used according to the present invention with acids, such as hydrogen fumarate, fumaric acid, tartaric acid, ethane-1,2-disulfonic acid, maleic acid, naphthalene-1,5-sulfonic acid, acetic acid, malic acid, lactic acid (i.e., L-lactic acid), succinic acid, salicylic acid, azelaic acid, 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, hydrochloric acid, dichloric acid, and citric acid, preferably hydrochloric acid, acetic acid, L-lactic acid, and maleic acid. In a further embodiment, the compounds of the present invention can be used as acid addition salts with itaconic acid, such as lefamulin itaconate (WO2021 / 209174).

[0041] In one preferred embodiment, the compound used according to the present invention is lefamulin in the form of lefamulin acetate.

[0042] Preferred crystalline forms of lefamulin, as well as crystalline salt forms of lefamulin, are disclosed in WO2011 / 146954A1, the contents of which are incorporated herein by reference. Among these, crystalline form B of lefamulin acetate as disclosed in WO2011 / 146954A1 is particularly preferred.

[0043] The compounds used according to the present invention, particularly lefamulin, can be used for the pharmaceutical treatments contemplated herein either alone or in combination with one or more other pharmaceutically active agents, including those used in the standard treatment of infections caused by F. tularensis, such as antibacterial compounds such as tetracyclines (e.g., doxycycline, tetracycline), aminoglycosides (e.g., streptomycin, gentamicin), fluoroquinolones (e.g., ciprofloxacin), or chloramphenicol.

[0044] Combinations include fixed combinations, in which two or more pharmaceutically active agents are present in the same formulation, kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g., with instructions for co-administration, and free combinations, in which the pharmaceutically active agents are packaged separately but with instructions for simultaneous or sequential administration.

[0045] Pharmaceutical compositions containing the compounds used according to the present invention, in particular lefamulin, may further comprise at least one pharmaceutically acceptable excipient, such as a carrier or diluent, for example, a filler, a binder, a disintegrant, a flow regulator, a lubricant, a sugar or sweetener, a flavoring, a preservative, a stabilizer, a wetting agent and / or an emulsifier, a solubilizer, a salt for regulating osmotic pressure and / or a buffer.

[0046] Such pharmaceutical compositions can be manufactured, for example, by conventional methods, for example, by mixing, granulating, coating, dissolving, spray-drying, or lyophilizing processes. A unit dosage form can contain, for example, from about 0.5 mg to about 3000 mg, for example, from 10 mg to about 600 mg.

[0047] [Example] The following abbreviations are used herein, including in the examples: ATCC American Type Culture Collection CAMHB Cation-Adjusted Mueller-Hinton Broth CFU colony forming unit CLSI Clinical Laboratory Standards Institute MIC minimum inhibitory concentration [μg / mL] MIC 50 MIC required to inhibit 50% of microbial growth MIC 90 MIC required to inhibit the growth of 90% of microorganisms SD standard deviation ssp. / subsp. subspecies (Example 1-In vitro antibacterial activity (MIC)) Objective: To test the antimicrobial susceptibility of lemfarin (BC-3781) and CLSI-compliant standard compounds against a diverse set of Francisella tularensis strains, including Francisella tularensis ssp. tularensis, F. tularensis ssp. holarctica, and F. tularensis ssp. novicida.

[0048] Methods: The minimum inhibitory concentration (MIC) of lefamulin (BC-3781) was determined at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) in accordance with CLSI guidelines (CLSI Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - Ninth Edition, CLSI document M07-A9, ISBN 1-56238-783-9, 2012; CLSI Performance Standards for Antimicrobial Susceptibility Testing; Eighteenth Informational Supplement. CLSI Document M100-S18, ISBN 1-56238-653-0, 2008; Johansson A. et al., J. Bacteriol., 2004, 186:5808-5818, DOI: Antibiotics were measured for each individual isolate using n = 15 F. tularensis isolates according to the protocol (10.1128 / JB.186.17.5808-5818.2004). Antibiotics were serially diluted two-fold in 50 μL of CAMHB. CAMHB was added with 2% Isovitalex (Becton Dickinson) in all steps using F. tularensis. The antibiotic range was 0.0039–8 μg / mL (ciprofloxacin) or 0.031–64 μg / mL (lefamulin, erythromycin) based on a final well volume of 100 μL after inoculation.

[0049] Plates were incubated at 35°C for 48 hours. MICs were determined both visually and spectrophotometrically. In cases of discrepancy between the visual and spectrophotometric MICs, the visual MIC was used in reporting and data analysis. All compounds were tested in the recommended CLSI quality control strains Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213, and Pseudomonas aeruginosa ATCC 27853 (data not shown).

[0050] 90% inhibition of bacterial growth (MIC) for the entire diversity set and subspecies 90 ) and 50% inhibition (MIC 50 The MIC of the antibiotic that produces the .

[0051] Results: Table 1 summarizes the in vitro antibacterial activities of lefamulin, erythromycin, and ciprofloxacin.

[0052] [Table 1]

[0053] Lefamulin demonstrated potent in vitro activity against a diverse set of F. tularensis strains (n ​​= 14), with MICs ranging from 0.5 to 8 μg / mL. Against F. tularensis subsp. tularensis (type A; n = 8), the most virulent of the F. tularensis subsp. tularensis subsp. tularensis, found primarily in North America and Mexico and responsible for the most severe human disease, lefamulin demonstrated MICs of 1 μg / mL and 1 μg / mL, respectively. 50 / 90 All tularensis subsp. isolates were inhibited at lefamulin concentrations of 4 μg / mL or less, including an MIC of 1 μg / mL against strain Schu4, the strain used to establish tularemia in vivo in animals (e.g., mice). Erythromycin showed somewhat weaker activity, with an MIC of 1 μg / mL. 50 / 90The MIC values ​​for ciprofloxacin were 0.016 μg / mL and 0.03 μg / mL against I. tularensis subsp. 50 / 90 The values ​​were shown.

[0054] Lefamulin showed MIC values ​​in the range of 0.5 to 8 μg / mL against F. tularensis subsp. holarctica (type B; n = 5), and MIC 50 Erythromycin (range 4 to ≥8 μg / mL, MIC 50 Similarly, lefamulin MIC values ​​were slightly higher against these less virulent type B strains than against F. tularensis subsp. tularensis (type A), as were 8 μg / mL. Ciprofloxacin showed comparable efficacy against isolates of subsp. tularensis and subsp. holarctica.

[0055] Lefamulin (MIC 2 μg / mL) and ciprofloxacin (MIC 0.016 μg / mL) showed potent activity against subspecies I. novicida, whereas erythromycin was inactive (MIC ≥ 8 μg / mL).

[0056] Example 2 - Evaluation of Lefamulin Dose on Survival of Mice Following F. tularensis Aerosol Exposure Objective: This study investigated the efficacy of lefamulin when administered to mice aerosol-challenged with the clinically useful F. tularensis subsp. tularensis SchuS4 strain.

[0057] method: Animals were aerosol challenged with the highly virulent SchuS4 strain (ITI3004) of F. tularensis subsp. tularensis. The bacterial concentration in the aerosol was serially diluted and plated. The actual challenge dose was the dose required to kill half of the test population (LD 50) was 76-fold higher than the baseline. 24 hours after challenge (PC), administration of the negative control (vehicle), ciprofloxacin control, and lefamulin was initiated (start of treatment). Administration was oral in a volume of 0.1–0.2 mL (depending on solubility / formulation). Lefamulin was diluted in water. The administration and treatment schedule is summarized in Table 2 below. All groups were administered for a total of 14 days and then observed for an additional 30 days (45 days post-challenge). This study included two different dosing regimens for lefamulin: a 75 mg / kg lefamulin group and a 150 / 75 mg / kg lefamulin group, with the latter receiving a higher initial dose on Day 1.

[0058] [Table 2]

[0059] Endpoint: Survival was assessed four times daily for the first 15 days of the study, and twice daily thereafter. On day 45 postchallenge, all surviving animals were euthanized for tissue burden determination. Animals were euthanized with carbon dioxide (CO2), and lungs and spleens were removed, weighed, and homogenized in 1 mL of sterile saline. The homogenates were serially diluted 1:10, and dilutions (100 μL) were plated in duplicate and incubated at 35°C for 48 hours to determine bacterial burden (note: the bacterial detection limit was 5 CFU / mL for spleen and lung).

[0060] result: Efficacy-survival results are summarized in Figure 1. In Figure 1, the small arrow indicates the start of treatment and the large arrow indicates the end of treatment.

[0061] The survival rate for lefamulin was significant (p<0.0008) in all dose groups when compared to the vehicle control (water for injection). Ten of 10 animals (100%) in the vehicle control group died by day 5, whereas 100% of the 150 / 75 mg / kg lefamulin and ciprofloxacin groups and 90% of the 75 mg / kg lefamulin group survived to the end of treatment (day 15). All treatment groups, including the lefamulin group and ciprofloxacin control, experienced nearly 100% mortality 5 days after the last dose and infection occurred after the end of treatment.

[0062] Bacterial burden was measured in animals that survived to day 45. The mean lung and spleen measurements for the remaining two ciprofloxacin-treated mice were 6.25 × 10 5 CFU / g and 4 × 10 6 CFU / g tissue. No ciprofloxacin resistance was detected. The lung and spleen counts of the remaining lefamulin-treated mouse were 1.3 x 10 6 CFU / g and 7.7 × 10 6 CFU / g. No resistance to lefamulin was detected.

[0063] Data from this study demonstrate that lefamulin and ciprofloxacin exhibited comparable efficacy against F. tularensis infection in a murine in vivo model. [Brief explanation of the drawings]

[0064] [Figure 1] Figure 1 shows the results of an in vivo study of mice challenged with an aerosol of F. tularensis subsp. tularensis SchuS4 at different oral doses of lefamulin (Lef), showing survival probability over time compared to untreated controls and ciprofloxacin (Cipro) treatment.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, prodrug or metabolite thereof, for use specifically in the treatment or prevention of bacterial infections mediated by F. tularensis. 【Chemical 1】 where n is 0 to 4; m is 0 or 1, provided that the sulfur atom and R ３ are located close to each other (when m is 0, R ３ is in the 2' position, and when m is 1, R ３ is in the 1' position); R is ethyl or vinyl; R １ is hydrogen or (C １－６ ) alkyl, R ２ is hydrogen or -(C ３－６ ) cycloalkyl, -unsubstituted (C １－６ ) alkyl, or one or more -hydroxy; preferably one or two -methoxy, halogens, and -(C ３－６ ) cycloalkyl, (C １－６ ) alkyl, or R １ and R ２ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring containing at least one nitrogen atom or one nitrogen and one additional heteroatom (e.g., selected from N or O), or R １ is hydroxy, and R ２ is formyl; R ３ OH, OR ４ , a halogen atom, or R ３ is bonded to 2', and p is 2 or 3; ２ ) ｐ represents —O—; R ４ is unsubstituted (C １－６ ) alkyl or (C ３－６ ) cycloalkyl.

2. 2. The compound for use according to claim 1, wherein the compound is selected from the group consisting of compounds of formula (II), (III), (IV), (V) and (VI): 【Chemistry 2】 where n, R in each case １ and R ２ is as defined in claim 1.

3. The compound is selected from the group: 14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, 14-O-{[(1S,2S,4S)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl-mutilin, 14-O-{[(1R,2R,5S)-5-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, 14-O-{[(1S,2S,5R)-5-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, 14-O-{[(1R,2R,4S)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4R) diastereomer, 14-O-{[(1R,2R,5R)-5-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, 14-O-{[(1S,2S,5S)-5-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, 14-O-{[(1R,2R,3R)-3-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,3S) diastereomer, 14-O-{[(1R,2R,4R)-4-diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4S) diastereomer, 14-O-{[(1R,2R,4R)-4-ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4S) diastereomer, 14-O-{[(1R,2R,5S)-5-ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5R) diastereomer, 14-O-{[(1R,2R,5S)-5-diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5R) diastereomer, 14-O-{[(1R,2R,4S)-4-diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4R) diastereomer, 14-O-{[(1R,2R,5R)-5-diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5S) diastereomer, 14-O-{[(1R,2R,3R)-3-ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,3S) diastereomer, 14-O-{[(1R,2R,3R)-3-diethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,3S) diastereomer, 14-O-{[(1R,2R,4S)-4-(formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4R) diastereomer, 14-O-{[(1R,2R,5S)-5-(formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5R) diastereomer, 14-O-{[(1R,2R,3R / S)-3-(formyl-hydroxy-amino)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,3R / S) diastereomer, 14-O-{[(1R,2R,5S)-2-hydroxy-5-methylamino-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5R) diastereomer, 14-O-{[(1R,2R,5S)-5-allylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5R) diastereomer, 14-O-{[(1R,2R,5S)-2-hydroxy-5-(2-methoxy-ethylamino)-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5R) diastereomer, 14-O-{[(1R,2R,4R*)-2-hydroxy-4-(2-hydroxy-ethylamino)-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4S*) diastereomer, 14-O-{[(1R,2R,4R*)-4-cyclohexylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4S*) diastereomer, 14-O-{[(1R,2R,4R*)-4-cyclopropylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4S*) diastereomer, 14-O-{[(1R,2R,5S*)-4-cyclopropylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5R*) diastereomer, 14-O-{[(1R,2R,4S*)-4-cyclopropylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,4R*) diastereomer, 14-O-{[(1R,2R,5R*)-2-hydroxy-5-morpholin-4-yl-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5S*) diastereomer, 14-O-{[(1R,2R,5S*)-2-hydroxy-5-morpholin-4-yl-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S,5R*) diastereomer, 14-O-{[(1R,2R,5S)-5-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-19,20-dihydro-mutilin and its (1S,2S,5R) diastereomer, 14-O-{[(1R,2R,5S)-5-ethylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-19,20-dihydro-mutilin and its (1S,2S,5R) diastereomer, 14-O-{[(1R,2R,5R)-5-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-19,20-dihydro-mutilin and its (1S,2S,5S) diastereomer, 14-O-{[(1R,2R)-4-aminomethyl-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S) diastereomer, 14-O-{[5-amino-2-chloro-cyclohexylsulfanyl]-acetyl}-mutilin, 14-O-{[4-amino-2-chloro-cyclohexylsulfanyl]-acetyl}-mutilin, 14-O-[(4-amino-1-hydroxy-cyclohexylmethylsulfanyl)-acetyl]-mutilin, 14-O-{[(1R,2R)-2-hydroxy-5-(3-methylamino-propyl)-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S) diastereomer, 14-O-{[(1R,2R)-2-hydroxy-4-(3-methylamino-propyl)-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S) diastereomer, 14-O-{[(1R,2R)-5-(3-amino-propyl)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S) diastereomer, 14-O-{[(1R,2R)-4-(3-amino-propyl)-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin and its (1S,2S) diastereomer, 14-O-{[(6R,8R)-8-amino-1,4-dioxa-spiro[4.5]dec-6-ylsulfanyl]-acetyl}-mutilin and its (6S,8S) diastereomer, 14-O-{[4-amino-2-methoxy-cyclohexylsulfanyl]-acetyl}-mutilin, and 14-O-{[5-amino-2-methoxy-cyclohexylsulfanyl]-acetyl}-mutilin, 3. The compound for use according to claim 1 or 2, selected from:

4. The compound for use according to any one of claims 1 to 3, wherein the compound is Lefamulin.

5. The compound for use according to any one of claims 1 to 4, wherein the compound is in the form of a salt and / or a solvate.

6. The compound for use according to any one of claims 1 to 5, wherein said compound is lefamulin in the form of lefamulin acetate.

7. A compound for use according to any of the preceding claims, wherein the bacterial infection is mediated by a subspecies of F. tularensis selected from the group consisting of F. tularensis subsp. tularensis (type A), F. tularensis subsp. holarctica (type B), and F. tularensis subsp. novicida.

8. 10. The compound for use according to any of the preceding claims, wherein the bacterial infection is tularemia.

9. 10. The compound for use according to any of the preceding claims, wherein said compound is used for post-exposure prophylaxis (PEP).

10. 10. The compound for use according to any of the preceding claims, wherein the compound is for oral administration.

11. A method for the treatment or prevention of bacterial infections mediated by F. tularensis, comprising administering to a subject in need of such treatment a compound as defined in any one of claims 1 to 6, in particular lefamulin, or a pharmaceutically acceptable salt, solvate, or ester of a metabolite thereof.

12. The method of claim 11 , wherein the subject is a human.

13. The method of claim 11 or 12, wherein the bacterial infection is mediated by a subspecies of F. tularensis selected from the group consisting of F. tularensis subsp. tularensis (type A), F. tularensis subsp. holarctica (type B), and F. tularensis subsp. novicida.

14. The method according to any one of claims 11 to 13, wherein the bacterial infection is tularemia.

15. The method according to any one of claims 11 to 14, wherein said method is for post-exposure prophylaxis (PEP).

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