Rifamycin analogs and antibody-drug conjugates thereof

Abstract

SOLUTION: The disclosure relates to rifamycin analog compounds, intermediates and precursors thereof, and pharmaceutical compositions capable of inhibiting bacterial growth (e.g., Staphylococcus aureus growth) and treating bacterial infections (e.g., Staphylococcus aureus infections). The disclosure further relates to rifamycin analog compounds and antibodies for inhibiting bacterial growth and treating bacterial infections, for example, antibodies specific for infectious disease-related targets such as membrane glycoprotein receptor (MSR1), wall teichoic acids (WTA) or Protein A, as well as methods of use thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 783,506, filed December 21, 2018, and U.S. Provisional Patent Application No. 62 / 844,860, filed May 8, 2019, the contents of which are incorporated herein by reference in their entireties.

[0002] Field of Disclosure The present disclosure relates to rifamycin analog compounds and pharmaceutical compositions thereof that can inhibit bacterial growth and inhibit bacterial infection, as well as antibody drug conjugates of rifamycin analog compounds with antibodies, e.g., antibodies specific for infectious disease-associated targets, and methods of use thereof.

[0003] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference. The ASCII copy, created on December 19, 2019, has the filename 250298_000145_SL.TXT and is 409,310 bytes in size. [Background technology]

[0004] Staphylococcus aureus (S. aureus) is a Gram-positive, round bacterium that belongs to the Firmicutes family and is a common member of the body's microbiota, often found in the upper respiratory tract and on the skin. It is a facultative anaerobe that is often catalase- and nitrate-reducing, and can grow without oxygen. S. aureus typically acts as a commensal of the human microbiota and can also be an opportunistic pathogen, a common cause of skin infections, including abscesses, respiratory infections, such as sinusitis, and food poisoning. Pathogenic strains often promote infection by producing virulence factors, including potent protein toxins, and by expressing cell surface proteins that bind and inactivate antibodies.

[0005] An estimated 20-30% of the human population are long-term carriers of Staphylococcus aureus, which can be found as part of the normal skin flora in the nares and as a resident of the female lower genital tract. S. aureus can cause a wide range of illnesses, from minor skin infections such as acne, impetigo, boils, cellulitis, folliculitis, carbuncles, scalded skin syndrome, and abscesses to life-threatening conditions such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome, bacteremia, and sepsis. S. aureus remains one of the top five causes of hospital-acquired infections and is a frequent cause of postoperative wound infections. Approximately 500,000 patients in U.S. hospitals each year are infected with staphylococcal infections, primarily caused by S. aureus. Up to 50,000 deaths in the U.S. each year are associated with S. aureus infections. Schlecht LM et al., 2015, Microbiology, 161, 1, 168-181. Despite much research and development, no vaccine for S. aureus is currently approved.

[0006] Penicillin was once the treatment of choice for Staphylococcus aureus infections. When penicillin was first introduced in 1943, antibiotic resistance in S. aureus was uncommon. By 1950, 40% of hospital isolates of S. aureus were penicillin resistant, and by 1960 this had risen to 80%. Chambers HF, 2001, Emerging Infectious Diseases, 7, 2, 178-82. Currently, S. aureus is resistant to many commonly used antibiotics.

[0007] The emergence of antibiotic-resistant strains of Staphylococcus aureus, such as methicillin-resistant Staphylococcus aureus (MRSA), is a global challenge in clinical medicine. While many MRSA strains are associated with hospitals and other institutions, they are becoming increasingly prevalent in community-acquired infections. MRSA is one of many threatening strains of Staphylococcus aureus that are resistant to most beta-lactam antibiotics. MRSA infections in both hospital and community settings are commonly treated with non-beta-lactam antibiotics, such as clindamycin (lincosamine) and cotrimoxazole (also known as trimethoprim / sulfamethoxazole). Resistance to these antibiotics has also led to the use of new broad-spectrum anti-Gram-positive antibiotics, such as linezolid, due to their efficacy as oral drugs. The current first-line treatment for serious invasive infections caused by MRSA is the glycopeptide antibiotics (vancomycin and teicoplanin). These antibiotics present many problems, including intravenous administration (oral preparations are not available), toxicity, and the need for regular monitoring of drug levels with blood tests. Furthermore, glycopeptide antibiotics do not penetrate infected tissues very well (which is of particular concern in infections of the brain and meninges, as well as endocarditis). Thus, there remains an unmet need for novel antibiotic treatments against S. aureus overall, and in the treatment of intracellular S. aureus infections specifically.

[0008] Rifamycins, a subclass of the ansamycin antibiotic family, are a group of antibiotics synthesized naturally by the bacterium Amycolatopsis rifamycinica or artificially. Rifamycins are particularly effective against mycobacteria and are therefore used to treat tuberculosis, leprosy, and Mycobacterium avium complex (MAC) infections. The rifamycin group includes the "classic" rifamycin drugs as well as the rifamycin analogs rifampicin (i.e., rifampin), rifabutin, rifapentine, rifalazil, and rifaximin. Rifamycin SV, sold under the brand name Aemcolo, is FDA-approved for the treatment of travelers' diarrhea in some circumstances.

[0009] Rifamycin class antibiotics inhibit bacterial RNA polymerase (RNAP) and have potent activity against Staphylococcus aureus. However, monotherapy with this class of antibiotics can result in the selection of resistant populations during treatment. Therefore, rifamycin antibiotics can be used in combination with first-line antibiotics to improve outcomes, which are common in infections involving prosthetics or external devices.

[0010] Macrophage scavenger receptor 1 (MSR1) is a single-pass trimeric type II transmembrane glycoprotein pattern recognition receptor (SSR1) that mediates the uptake of a range of negatively charged / polyanionic ligands, including modified low-density lipoprotein (LDL) (Krieger, M. 1994. Annu. Rev. Biochem. 63:601-637; Platt, N. and S. Gordon. 2001. J Clin Invest. 108(5):649-654) and advanced glycation end products of bovine serum albumin (AGE-BSA) (Smedsrod et al. 1997. Biochem J. 322(Pt 2):567-573). The MSR1 receptor is involved in many macrophage-related physiological and pathological processes, including atherosclerosis, Alzheimer's disease, and host defense.

[0011] MSR1 expression was originally considered specific to macrophages. However, recent evidence has demonstrated its presence on different classes of dendritic cells (Herber et al. 2010. Nat. Med. 16(8):880-886). In addition, MSR1 is thought to be expressed in endothelial cells and smooth muscle cells. MSR1 is internalized to the cell surface via coated pits, releases its ligand at acidic pH, and then recycles back to the cell surface via the trans-Golgi apparatus (Doi et al. 1994. Journal of Biological Chemistry; Mori, T. 1994. Lab Invest.). This promotes the transformation of monocyte-derived macrophages into foam cells, a critical step in the progression of atherosclerosis.

[0012] Staphylococcus aureus is a facultative intracellular bacterium that can survive phagocytosis by macrophages and other cell types (Horn et al. 2018. Int. J. Med. Microbiol. 308(6):607-624; Jubrail et al. 2016. Cell Microbiol. 18(1):80-96; Mitchell et al. 2016. Microbiol. Spectr. 4(3)). In vivo imaging has demonstrated that macrophages can function as reservoirs where S. aureus replicates and disseminates for other periods during infection (Surewaard et al. 2016. J. Exp. Med. 213(7):1141-51). Most antibiotics do not penetrate well into cells, including macrophages, suggesting that intracellular S. aureus reservoirs may evade treatment with standard-of-care antibiotics (Lehar et al. 2015. Nature. 527(7578):323-8). However, liposomal formulations of vancomycin improved antibiotic penetration into macrophages and reduced S. aureus organ burden more efficiently than standard-of-care vancomycin (Surewaard et al. 2016. J. Exp. Med. 213(7):1141-51). Collectively, these data suggest that antibiotic delivery to macrophages may be an effective method for eliminating intracellular S. aureus reservoirs.

[0013] Teichoic acids are phosphate-rich molecules found in many glycan-binding proteins within the cell walls of most Gram-positive bacteria, including Staphylococcus aureus. Teichoic acids, along with many other glycoproteins, form a thick layer of peptidoglycan sheath around the bacterium, which not only stabilizes the cell membrane but also provides numerous sites for the attachment of other molecules. Wall teichoic acids ("WTA") are a type of teichoic acid that are covalently linked to peptidoglycan and extend through the cell wall. WTA can account for as much as 60% of the total cell wall mass in glycan-binding proteins. As a result, WTA represent highly expressed cell surface antigens on Gram-positive bacteria, including Staphylococcus aureus.

[0014] S. aureus further expresses numerous surface determinant antigens, including S. aureus protein A (SpA), polysaccharide poly-N-acetylglucosamine (PNAG), iron-regulated surface determinant proteins IsdA, IsdB, IsdC, IsdE, and IsdH, clumping factor proteins ClfA and ClfB, capsular polysaccharide (CP) type 5, CP8, serine-aspartic acid repeat proteins SdrC, SdrD, and SdrE, fibronectin-binding proteins A and B (FnBpA and FnBpB), Cna (collagen-binding protein), and SasG (S. aureus surface protein G). These surface antigens play roles in host tissue colonization, evasion of the host immune response, and bacterial fitness.

[0015] Therefore, the development of ADCs containing rifamycin analogs allows for target-specific delivery of rifamycin analogs inside macrophage cells or immobilization of rifamycin analogs on the surface of bacteria.Furthermore, such ADCs may also have improved activity against resistant bacterial targets, improved bioavailability, and improved therapeutic range.Therefore, there remains a need for effective treatment of antibiotic-resistant bacteria using antibody-drug conjugates of rifamycin analogs.

[0016] Thus, there remains an unmet need to develop effective analogs of rifamycin to address the problem of the proliferation of antibiotic-resistant bacteria, including antibiotic-resistant Staphylococcus aureus strains. MSR1 antibodies may provide a means for specific targeting of therapeutic molecules, such as rifamycin analogs, to minimize unwanted side effects resulting from systemic administration of such compounds and to aid in the internalization of these compounds into macrophage cells. Alternatively, conjugation to antibodies targeting cell surface antigens (e.g., WTA, Protein A) may improve the therapeutic efficacy of rifamycin analogs.

[0017] The foregoing discussion is presented merely to provide a better understanding of the nature of the problems faced in the art and is not intended as an admission of prior art, nor should citation of any reference herein be construed as an admission that such reference constitutes "prior art" to the instant application. Summary of the Invention

[0018] As discussed herein, there exists a need to develop effective treatments for bacterial infections generally, and Staphylococcus aureus infections in particular. The present disclosure addresses these and other needs by providing new rifamycin analog compounds, their intermediates and precursors, antibody-drug conjugates, pharmaceutical compositions, and methods of treatment using such compounds and pharmaceutical compositions.

[0019] Various non-limiting aspects and embodiments are described below.

[0020] In one aspect, the disclosure provides a rifamycin analog compound having the structure of formula (A), or an intermediate or precursor thereof, or a pharmaceutically acceptable salt thereof:

[0021] [ka] During the ceremony, X is -O- and -NR * - selected from Za and Zb are independently hydrogen, -Cl, -Br, -OR1, and -R N wherein at least one of Za or Zb is not hydrogen; and wherein R1 is hydrogen, R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * ,-(C=O)-NH2,-(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0022] [ka] is selected from, where the symbol

[0023] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbon, and fluorenylmethyloxycarbonyl (F MOC ) and tert-butyloxycarbonyl (B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbons, and -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR *and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0024] In one aspect, the disclosure provides a rifamycin analog compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0025] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R *, -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0026] [ka] is selected from, where the symbol

[0027] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R *each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0028] In one aspect, the disclosure provides a rifamycin analog compound having the structure of formula (I'), or a pharmaceutically acceptable salt thereof:

[0029] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * ,-SCN,-NCS,-NSO,-SSR * , -SO2R* , -SO2N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0030] [ka] is selected from, where the symbol

[0031] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R *, -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0032] In some embodiments of the compound of Formula (A), (I), or (I′), X is —O—, R is an aliphatic C-C hydrocarbon, R is a methyl group, R is Ac(—(C═O)—CH), R is hydrogen, and R a is hydrogen.

[0033] In some embodiments of a compound of Formula (A), (I), or (I′), X is —O—, R is a benzyl group, R is a methyl group, R is Ac(—(C═O)—CH), R is hydrogen, and R a is hydrogen and R b is hydrogen.

[0034] In some embodiments of a compound of Formula (A), (I), or (I′), X is —O—, R1 is an aliphatic C1-C8 hydrocarbon containing 1 to 8 heteroatoms selected from O and N, R2 is a methyl group, R3 is Ac(—(C═O)—CH3), R4 is hydrogen, and R a is hydrogen and R b is hydrogen.

[0035] In some embodiments of the compound of Formula (A), (I), or (I′), X is —O— and R 1 is —NH 2 , —NHR * , -N(R * )2, and R * is hydrogen or an aliphatic C1-C3 hydrocarbon, R2 is a methyl group, R3 is Ac(-(C=O)-CH3), R4 is hydrogen, and R a is hydrogen and R b is hydrogen.

[0036] In some embodiments of a compound of Formula (A), (I), or (I′), X is —NCH—, R is —OH, R is a methyl group, R is Ac(—(C═O)—CH), R is hydrogen, and R a is hydrogen and R b is hydrogen.

[0037] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (II):

[0038] [ka] During the ceremony, X is -O- and -NR * - selected from R a are hydrogen, -Cl, and -OR * is selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R *)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group; R N teeth,

[0039] [ka] is selected from, where the symbol

[0040] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0041] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (II'):

[0042] [ka] During the ceremony, X is -O- and -NR * - selected from R a is hydrogen and -OR * is selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group; R N teeth,

[0043] [ka] is selected from, where the symbol

[0044] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0045] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (III):

[0046] [ka] During the ceremony, R ais hydrogen and -OR * is selected from R5 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R5 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof, provided that R5 is not an n-butyl group; R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and R N teeth,

[0047] [ka] is selected from, where the symbol

[0048] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure.

[0049] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (III'):

[0050] [ka] During the ceremony, R a is hydrogen and -OR * is selected from R5 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R5 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof, provided that R5 is not an n-butyl group; R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and R N teeth,

[0051] [ka] is selected from, where the symbol

[0052] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure.

[0053] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (IV):

[0054] [ka] During the ceremony, R a is hydrogen and -OR * is selected from R5 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R5 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R* , -CHO, -CO2H, -CO2R * and combinations thereof; R N teeth,

[0055] [ka] is selected from, where the symbol

[0056] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0057] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (IV'), or a pharmaceutically acceptable salt thereof:

[0058] [ka] During the ceremony, R a is hydrogen and -OR * is selected from R5 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R5 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof; R N teeth,

[0059] [ka] is selected from, where the symbol

[0060] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0061] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (V):

[0062] [ka] During the ceremony, X is -O- and -NR * - selected from R a is hydrogen and -OR * is selected from R6 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R6 is selected from -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof, provided that R6 is not an n-butyl group; R N teeth,

[0063] [ka] is selected from, where the symbol

[0064] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OCor R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0065] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (V'), or a pharmaceutically acceptable salt thereof:

[0066] [ka] During the ceremony, X is -O- and -NR * - selected from R a is hydrogen and -OR * is selected from R6 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R6 is selected from -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R *, -CHO, -CO2H, -CO2R * and combinations thereof, provided that R6 is not an n-butyl group; R N teeth,

[0067] [ka] is selected from, where the symbol

[0068] [ka] represents the attachment point, R', R", and R'" are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0069] In another aspect, the disclosure provides a rifamycin analog compound having the structure of formula (B), or an intermediate or precursor thereof, or a pharmaceutically acceptable salt thereof:

[0070] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is hydrogen, R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR* , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0071] [ka] is selected from, where the symbol

[0072] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbon, and fluorenylmethyloxycarbonyl (F MOC ) and tert-butyloxycarbonyl (B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbons, and -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R *)2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0073] In another aspect, the present disclosure provides a rifamycin analog compound having the structure of formula (B-1), or a pharmaceutically acceptable salt thereof:

[0074] [ka] During the ceremony, X is -O- and -NR* - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group; RN teeth,

[0075] [ka] is selected from, where the symbol

[0076] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0077] In another aspect, the present disclosure provides a rifamycin analog compound having the structure of formula (B-2), or a pharmaceutically acceptable salt thereof:

[0078] [ka] During the ceremony, R N teeth,

[0079] [ka] is selected from, where the symbol

[0080] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure.

[0081] In another aspect, the present disclosure provides a rifamycin analog compound having the structure of formula (B-2), or a pharmaceutically acceptable salt thereof:

[0082] [ka] During the ceremony, R N teeth

[0083] [ka] where the symbol

[0084] [ka] represents a point of attachment, and R' and R" are selected from hydrogen and C1-C6 aliphatic hydrocarbons.

[0085] In one embodiment, the rifamycin analog compound has a structure according to the following formula:

[0086] [ka]

[0087] In any embodiment of the preceding formula, R is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-3 heteroatoms selected from O and N, wherein R is -F, -Cl, -Br, -I, -OH, C 1-3 Alkoxide, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -O-(C=O)-H, -O-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group and that when X is -O-, R1 is not hydrogen.

[0088] In any embodiment of the preceding formula, R is an aliphatic C-C 20 Hydrocarbons and aromatics C1-C 20 Compounds are provided that are in combination with hydrocarbons.

[0089] In any embodiment of the preceding formula, R is an aliphatic C-C 20 Hydrocarbons and heteroaromatic C1-C20 Compounds are provided that are in combination with hydrocarbons.

[0090] In embodiments of any of the above formulas, compounds are provided in which R 1 is selected from the following:

[0091] [ka]

[0092] In any embodiment of the preceding formula, R1 is -NH2, -NHR * , -N(R * )2, or -N(R * )-(C=O)-R * Aliphatic C1-C substituted with one or more of 20 A compound is provided that is a hydrocarbon.

[0093] In embodiments of any of the preceding formulas, R1 is an aliphatic C1-C2 substituted with -NH-(C=O)-CH3 or -N(CH3)-(C=O)-CH3. 20 A compound is provided that is a hydrocarbon.

[0094] In any embodiment of the preceding formula, R a is hydrogen.

[0095] In any embodiment of the preceding formula, R a is -OH.

[0096] In any embodiment of the preceding formula, R a is -Cl.

[0097] In any embodiment of the preceding formula, R a -OR * and R * Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 A compound selected from the group consisting of: a cyclohexanediol, ...

[0098] In any embodiment of the preceding formula, R N is selected from the following:

[0099] [ka] In the formula, the symbol

[0100] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure.

[0101] In any embodiment of the preceding formula, R N is selected from the following:

[0102] [ka] wherein R' is hydrogen, an aliphatic hydrocarbon, or a protecting group, and wherein the symbol

[0103] [ka] represents the point of attachment.

[0104] In any embodiment of the preceding formula, R * are independently, when each occurs, selected from hydrogen, aliphatic C1-C6 hydrocarbons, aromatic C4-C6 hydrocarbons, and combinations thereof, which optionally contain 1 to 3 heteroatoms selected from O, N, and combinations thereof.

[0105] In one embodiment, a rifamycin analog compound of the present disclosure has a structure selected from the group consisting of:

[0106] [ka]

[0107] [ka]

[0108] [ka]

[0109] [ka]

[0110] In one embodiment, a rifamycin analog compound of the present disclosure has a structure selected from the group consisting of:

[0111] [ka]

[0112] In one aspect, the disclosure provides a method of making a rifamycin analog compound having the structure of formula (V), or a pharmaceutically acceptable salt thereof:

[0113] [ka] In the formula, X is —O— and —NR * - selected from R6 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof; R N teeth,

[0114] [ka] is selected from, where the symbol

[0115] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0 to 8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, said method comprising: (a) Rifamycin S, having the following structure:

[0116] [ka] with a compound having the structure of formula (VI):

[0117] [ka] In the formula, X' is -OH and -NHR * and (b) treating the product of step (a) with an oxidizing agent; Includes.

[0118] In one aspect, the disclosure provides a method of making a rifamycin analog compound having the structure of formula (V'), or a pharmaceutically acceptable salt thereof:

[0119] [ka] In the formula, X is —O— and —NR * - selected from R6 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof; R N teeth,

[0120] [ka] is selected from, where the symbol

[0121] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0 to 8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, said method comprising: (a) Rifamycin S, having the following structure:

[0122] [ka] with a compound having the structure of formula (VI'):

[0123] [ka] In the formula, X' is -OH and -NHR * and (b) treating the product of step (a) with an oxidizing agent; Includes.

[0124] In one aspect, the disclosure provides a method of making a compound having the structure:

[0125] [ka] The method comprises: (a) contacting Rifamycin S with a compound having the structure of formula (VII),

[0126] [ka] wherein PG is a protecting group; (b) treating the product of step (a) with an oxidizing agent; (c) removing the protecting group PG; Includes.

[0127] In one embodiment, the compound of formula (VII) is prepared by removing the protecting group PG′ from a compound of formula (VIII):

[0128] [ka] In the formula, the protecting groups PG and PG' may be the same or different.

[0129] In one embodiment, the compound of formula (VIII) is a compound of formula (IX)

[0130] [ka] with a compound of formula (X),

[0131] [ka] In the formula, the protecting groups PG and PG' may be the same or different.

[0132] In one aspect, the disclosure provides a method of making a compound having a structure of formula (XI), or a pharmaceutically acceptable salt thereof:

[0133] [ka] In the formula, R6 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; R6 is selected from -F-Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , CHO, -CO2H, -CO2R * , -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * Optionally substituted with one or more of: -CF, -O-CF, and combinations thereof; R N teeth,

[0134] [ka] is selected from, where the symbol

[0135] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OCor R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and a combination thereof, which further comprises 0 to 8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, and the method comprises producing a compound having the structure of formula (XII):

[0136] [ka] with an alcohol having the structure R6-OH.

[0137] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XIII), or a pharmaceutically acceptable salt thereof:

[0138] [ka] where A is a single bond (A is absent) or an aliphatic C1-C 20 selected from hydrocarbons, R cy is a C3-C alkyl group further containing 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; 14 alicyclic hydrocarbons, where R cy is -F, -Cl, -Br, I, -OH, -OR *, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; The method comprises:

[0139] [ka] and Structure R cy The method includes a step of contacting the compound with an alcohol having the formula -A-OH.

[0140] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XIII'), or a pharmaceutically acceptable salt thereof:

[0141] [ka] where A is a single bond (A is absent) or an aliphatic C1-C 20 selected from hydrocarbons, R cy is a C3-C alkyl group containing 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; 14 alicyclic hydrocarbons, where R cy is -F, -Cl, -Br, I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR* , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; The method comprises:

[0142] [ka] and Structure R cy The method includes a step of contacting the compound with an alcohol having the formula -A-OH.

[0143] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XIV), or a pharmaceutically acceptable salt thereof:

[0144] [ka] wherein Y, at each occurrence, is selected from -O- and -NR'R"-; n, at each occurrence, is an integer from 1 to 6; and R', R", and R'" are each independently selected from hydrogen, aliphatic C1-C 20 selected from hydrocarbons, The method comprises:

[0145] [ka] and structure R”R'NY-(CH2) n -Y-(CH2) n The method includes contacting the compound with an alcohol having an —OH group.

[0146] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XIV'), or a pharmaceutically acceptable salt thereof:

[0147] [ka] wherein Y, at each occurrence, is selected from -O- and -NR'R"-; n, at each occurrence, is independently an integer from 1 to 6; and R', R", and R'" are each independently selected from hydrogen and aliphatic C1-C 20 selected from hydrocarbons, The method comprises:

[0148] [ka] and structure R”R'NY-(CH2) n -Y-(CH2) n The method includes contacting the compound with an alcohol having an —OH group.

[0149] In one embodiment, the compound of formula (XII) is prepared by contacting rifamycin S with 2-amino-5-bromophenol and treating the resulting product with an oxidizing agent.

[0150] In one embodiment, the compound of formula (XII') is prepared by contacting rifamycin S with 2-amino-4-bromophenol and treating the resulting product with an oxidizing agent.

[0151] In one aspect, the disclosure provides a pharmaceutical composition comprising one or more compounds as described above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0152] In another aspect, the disclosure provides a pharmaceutical dosage form comprising one or more of the compounds as described above or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described above.

[0153] In another aspect, the disclosure provides a method for preventing or inhibiting bacterial growth, the method comprising administering an effective amount of a rifamycin analog compound having a structure according to any one of formulas (A), (B), (I), (I'), (II), (II'), (III), (III'), (IV), (IV'), (V), or (V').

[0154] In one embodiment, the bacterium is a gram-positive bacterium.

[0155] In one embodiment, the bacterium is penicillin-resistant.

[0156] In one embodiment, the bacterium is Staphylococcus aureus.

[0157] In one embodiment, the bacterium is methicillin-resistant Staphylococcus aureus (MRSA).

[0158] In one embodiment, the bacterium is vancomycin-resistant Staphylococcus aureus (VRSA).

[0159] In one embodiment, the bacterium is methicillin-sensitive Staphylococcus aureus (MSSA).

[0160] In yet another aspect, the disclosure provides a method of treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of a rifamycin analog compound having a structure according to any one of formulas (A), (B), (I), (I'), (II), (II'), (III), (III'), (IV), (IV'), (V), or (V').

[0161] In one embodiment, the bacterial infection is a gram-positive infection.

[0162] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[0163] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[0164] In one embodiment, the bacterial infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection.

[0165] In one embodiment, the bacterial infection is a vancomycin-resistant Staphylococcus aureus (VRSA) infection.

[0166] In one embodiment, the bacterial infection is a methicillin-sensitive Staphylococcus aureus (MSSA) infection.

[0167] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[0168] In one embodiment, the subject is a human.

[0169] In one embodiment, the method further comprises administering a second therapeutic agent.

[0170] In one embodiment, the second therapeutic agent is a second antibiotic.

[0171] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[0172] In one embodiment, the second antibiotic is selected from an aminoglycoside, a beta-lactam, a macrolide, a cyclic peptide, a tetracycline, a fluoroquinoline, a fluoroquinolone, and an oxazolidinone.

[0173] In one embodiment, the second antibiotic is selected from clindamycin, novobiocin, retapamulin, daptomycin, sitafloxacin, teicoplanin, triclosan, naphthyridone, radezolid, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin.

[0174] In one embodiment, the compound is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[0175] In another aspect, provided herein is an antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof, wherein the antibody-drug conjugate further comprises a rifamycin analog. In some embodiments of the antibody-drug conjugate of the present invention, the antibody or antigen-binding fragment thereof binds to an infectious disease-related target. Infectious disease-related targets useful in the present disclosure include, but are not limited to, macrophage scavenger receptor 1 (MSR1), wall teichoic acid (WTA), Staphylococcus aureus antigens such as protein A, IsdA, IsdB, IsdC, IsdE, IsdH, ClfA, ClfB, CP5, CP8, SdrC, SdrD, SdrE, FnBpA, FnBpB, Cna, polysaccharide poly-N-acetylglucosamine (PNAG), and SasG.

[0176] In some embodiments, the antibody or antigen-binding fragment thereof binds to MSR1. In some embodiments, the antibody or antigen-binding fragment thereof binds to WTA. In some embodiments, the antibody or antigen-binding fragment thereof binds to Protein A.

[0177] In another aspect, provided herein is an antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof, which binds to a membrane glycoprotein receptor known as MSR1, and further comprises a rifamycin analog. The antibody is useful, inter alia, for targeting cells, such as macrophage cells, that express MSR1.

[0178] In another aspect, provided herein is an antibody drug conjugate comprising an antibody or antigen-binding fragment thereof, wherein the antibody drug conjugate is bound to wall teichoic acid (WTA) and further comprises a rifamycin analog.

[0179] In another aspect, provided herein is an antibody drug conjugate comprising an antibody or antigen-binding fragment thereof, wherein the antibody drug conjugate is bound to Protein A and further comprises a rifamycin analog.

[0180] In another aspect, a pharmaceutical composition is provided comprising an antibody-drug conjugate, the antibody-drug conjugate comprising a recombinant human antibody or fragment thereof, the pharmaceutical composition further comprising a rifamycin analog and a pharmaceutically acceptable carrier. In some embodiments, the recombinant human antibody or fragment thereof specifically binds to an infectious disease-related target. In some embodiments, the recombinant human antibody or fragment thereof specifically binds to MSR1, WTA, or Protein A. In a related aspect, an embodiment relates to a composition that is a combination of an antibody-drug conjugate comprising an antibody described herein, the composition further comprising a rifamycin analog and a second therapeutic agent. In one embodiment, the second therapeutic agent is any agent that is advantageously used in combination with an antibody-drug conjugate comprising an antibody described herein. In one embodiment, the second therapeutic agent is an antibody-drug conjugate comprising an antibody described herein conjugated to a second drug or therapeutic agent. Exemplary combination therapies, co-administration formulations, and ADCs involving antibodies are disclosed elsewhere herein.

[0181] Further provided herein are reactive linker payloads comprising rifamycin analogs, e.g., compounds having a structure according to embodiments of Formula (A), (B), (I), (I'), (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (B-1), and (B-2) as provided herein, which are useful for preparing antibody-drug conjugates comprising substitutions. Further provided herein are modified antibodies and modified antigen-binding fragments useful for preparing antibody-drug conjugates comprising rifamycin analogs. In some embodiments, the antibodies or antigen-binding fragments thereof specifically bind to an infectious disease-associated target. In some embodiments, the antibodies or antigen-binding fragments thereof specifically bind to MSR1, WTA, or Protein A.

[0182] Further provided herein are methods for preventing or inhibiting bacterial growth, comprising administering an effective amount of an antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof and a rifamycin analog. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to an infectious disease-associated target. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to MSR1, WTA, or Protein A.

[0183] Further provided herein are therapeutic methods comprising administering to a subject an effective amount of an ADC comprising an antibody, or antigen-binding fragment thereof, and a rifamycin analog. The therapeutic method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an ADC comprising an antibody, or antigen-binding fragment thereof, and a rifamycin analog. The disorder being treated is any disease or condition that is improved, ameliorated, inhibited, or prevented by targeting an infection-associated target and / or administering an antibiotic agent. In some embodiments, the disease or condition is a proliferative disease, metabolic disease, inflammation, neurodegenerative disease, or a disease, disorder, or condition associated with glucocorticoid receptor signaling. In some such embodiments, side effects associated with administering an unconjugated rifamycin analog are reduced. Provided herein are uses of an antibody, or antigen-binding fragment thereof, or an ADC comprising the antibody, or antigen-binding fragment thereof, for the treatment of a disease, disorder, or condition described herein. In some embodiments, the antibody, or antigen-binding fragment thereof, specifically binds to an infection-associated target. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to MSR1, WTA, or Protein A.

[0184] Further provided herein are methods for treating a disease, disorder, or condition associated with a staphylococcal infection, e.g., a Staphylococcus aureus infection, and / or ameliorating at least one symptom associated with the disease, disorder, or condition, comprising administering to a subject a rifamycin analog or an ADC comprising an antibody or antigen-binding fragment thereof. The disease, disorder, or condition can be cellulitis, bacteremia, skin necrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boil, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, post-burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, or septic arthritis. In some embodiments, the subject has a prosthetic joint, and the rifamycin analog or an ADC comprising the antibody or antigen-binding fragment thereof, and the rifamycin analog disclosed herein, are used to treat and / or prevent a Staphylococcus aureus infection in tissues surrounding the prosthetic joint. In some embodiments, the subject has a catheter, and an ADC comprising a rifamycin analog or an antibody or antigen-binding fragment thereof, and a rifamycin analog disclosed herein are used to treat and / or prevent Staphylococcus aureus infection of the catheter and / or tissue surrounding the catheter. In some embodiments, the subject has an implanted foreign body, and an ADC comprising a rifamycin analog or an antibody or antigen-binding fragment thereof, and a rifamycin analog disclosed herein are used to treat and / or prevent Staphylococcus aureus infection of the foreign body and / or tissue surrounding the foreign body. In some embodiments, the subject has mastitis, and the antibodies disclosed herein are useful for treating mastitis. The method of treatment comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a rifamycin analog or an ADC comprising an antibody or antigen-binding fragment thereof and a rifamycin analog. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to an infection-associated target. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to MSR1, WTA, or Protein A.

[0185] In another aspect, the present disclosure provides an antibody drug conjugate comprising an antibody or antigen-binding fragment thereof conjugated by a linker or linker-spacer to a rifamycin analog compound according to any of the embodiments of the present disclosure.

[0186] In various embodiments, the antibody or antigen-binding fragment thereof binds to macrophage scavenger receptor 1 (MSR1). In various embodiments, the antibody or antigen-binding fragment thereof binds to wall teichoic acid (WTA). In various embodiments, the antibody or antigen-binding fragment thereof binds to Staphylococcus aureus protein A.

[0187] In one embodiment, the antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 9, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 9.

[0188] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 46, 62, 102, and 294; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 48, 64, 104, and 296; May include:

[0189] In one embodiment, an anti-WTA antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 2A, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 2A.

[0190] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 470, 476, 482, and 488; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 471, 477, 483, and 489; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 472, 478, 484, and 490; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 467, 473, 479, and 485; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 468, 474, 480, and 486; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 469, 475, 481, and 487; May include:

[0191] In one embodiment, an anti-WTA antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 2B, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 2B.

[0192] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, and 574; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, and 575; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576, and 584; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565, and 571; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566, and 572; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567, and 573; May include:

[0193] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation (EU numbering) in the light chain.

[0194] In one embodiment, an anti-Protein A antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 3A, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 3A.

[0195] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 632, 652, and 672; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 634, 654, and 674; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 636, 656, and 676; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 640, 660, and 680; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 642 and 662; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 644, 664, and 683; May include:

[0196] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises H435R and Y436F mutations (EU numbering) in the heavy chain Fc.

[0197] In various embodiments, the antibody or antigen-binding fragment thereof comprises a C103S mutation in the light chain.

[0198] In various embodiments, the antibody or antigen-binding fragment thereof is conjugated to a compound of the present disclosure at position 103 of the light chain.

[0199] In one embodiment, the linker or linker spacer is selected from the following:

[0200] [ka]

[0201] In another aspect, the present disclosure provides an antibody drug conjugate having a structure according to formula (XVIII):

[0202] [ka] During the ceremony, BA is an antibody or antigen-binding fragment thereof RG is a reactive group selected from maleimide, N-hydroxysuccinimide, or succinimide; SP does not exist or C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH-, -(CH) u -C(O)-NH-, (-CH2-CH2-O) e , -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v -, -(CH) u -C(O)-NH-(CH2-CH2-O)e-(CH) u a residue of a spacer group selected from the group consisting of -C(O)-NH-, -(CH)-C(O)-NH-(CH-CH-O)-(CH)-C(O)-NH-, and combinations thereof, wherein, independently at each occurrence, subscript e is an integer from 0 to 20, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8; AA is a linker selected from valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, or glycine-valine; B does not exist, or

[0203] [ka] and

[0204] [ka] indicates the atom to which B is attached to the adjacent group in the formula: n is an integer from 1 to 30, and PA is a rifamycin analog according to any of the embodiments of the present disclosure.

[0205] In one embodiment,

[0206] [ka] teeth,

[0207] [ka] is.

[0208] In one embodiment,

[0209] [ka] teeth,

[0210] [ka] is.

[0211] In one embodiment,

[0212] [ka] teeth,

[0213] [ka] is.

[0214] During the ceremony,

[0215] [ka] is the bond to an antibody or antigen-binding fragment thereof. In one aspect, the present disclosure provides an antibody drug conjugate having a structure according to formula (XIX):

[0216] [ka] During the ceremony, BA is an antibody or antigen-binding fragment thereof RG is selected from maleimide, N-hydroxysuccinimide, or succinimide; SP 1 and SP 2 is independently absent or C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH-

[0217] [ka] , -(CH) u -C(O)-NH-, (-CH2-CH2-O) e , -NH-CH2-NH-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v -, ... AA is a linker selected from valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, or glycine-valine; PEG is a polyethylene glycol chain containing 1 to 30 polyethylene glycol residues; B does not exist, or

[0218] [ka] and

[0219] [ka] indicates the atom to which B is attached to the adjacent group in the formula: n is an integer from 1 to 30, m is an integer from 0 to 20, and PA is a rifamycin analog according to any of the embodiments of the present disclosure.

[0220] In one embodiment,

[0221] [ka] teeth,

[0222] [ka] is.

[0223] In one aspect, the present disclosure provides an antibody drug conjugate comprising an antibody or antigen-binding fragment thereof conjugated via a linker or linker-spacer to a rifamycin analog payload having the structure of formula (XX):

[0224] [ka] During the ceremony, X is -O-, -S-, and -NR * - selected from Za is -OR1 and -R N is selected from R1 is a single bond, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and R is selected from -F, -Cl, -Br, -I, -OH, -OR. * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R* , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * Optionally substituted with one or more of: -CF, -O-CF, and combinations thereof; R N teeth,

[0225] [ka] is selected from, where the symbol

[0226] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently straight-chain, branched-chain, or cyclic aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a are independently hydrogen, -F, -Cl, -Br, -I, -OH, OR when present. * , -NH2, -NHR * , -N(R * )2, -N(R * )3+ , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, and the group Za is attached to a linker.

[0227] It is understood that the group R1 is either a single bond (R1 is absent) or a divalent group, ie, an R1 that can be attached to the -O- of the rifamycin analog as well as to a linker.

[0228] In one embodiment, -OR1 is -O- (R1 is absent),

[0229] [ka] is.

[0230] In one embodiment, X is -O- and -OR1 comprises a tertiary amine. In some such embodiments, -OR1 is

[0231] [ka] is.

[0232] In some embodiments, the antibody-drug conjugate comprising a linker-rifamycin analog payload comprises an ammonium salt with one or more counterions. Any pharmaceutically acceptable counterion may be suitable. For example, in embodiments of the present disclosure, a suitable counterion is F - , Cl - , Br - , I - , O.H. - , - BF4, CF3SO3 - , monobasic sulfate, dibasic sulfate, monobasic phosphate, dibasic phosphate, tribasic phosphate, NO3 - , PF6 - , NO2 - , carboxylate, C e F f SO3 - (e=2-10, f=2e+1), acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, camsylate, carbonate, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollyalarsanilate, hexanoate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, mucate, napsylate, oleate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, tosylate, or triethiodide.

[0233] In some embodiments, R a is absent. In some embodiments, R a is -OH and is present in one occurrence.

[0234] In one aspect, the present disclosure provides an antibody or antigen-binding fragment thereof conjugated via a linker or linker-spacer to a rifamycin analog having the structure of formula (XXI):

[0235] [ka] During the ceremony, X is -O-, -S-, and -NR * - selected from R5 is an aliphatic C1-C further containing 0-8 heteroatoms selected from a single bond, halogen, O, N, and S. 20 hydrocarbons,

[0236] [ka] where Y is C or N; R2, R3, and R4 are independently hydrogen, straight-chain, branched-chain, or cyclic aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; and R 5c is a single bond or an aliphatic C1-C8 hydrocarbon, where the group R5 is attached to the linker.

[0237] It is understood that the group R5 is either a single bond (R5 is absent) or a divalent group, i.e., an R5 that can be attached to a linker as well as the -O- of a rifamycin.

[0238] In one embodiment, -OR5 is -O- (R5 is absent),

[0239] [ka] is.

[0240] In one embodiment, X is O and -OR5 comprises a tertiary amine. In some such embodiments, -OR5 is

[0241] [ka] is.

[0242] In one embodiment of any of the above, R2 is methyl, ethyl, propyl, or isopropyl, R3 is a CH3-(C=O)-(acetyl) group, CH3CH2-(C=O)-, CH3CH2CH2-(C=O)-, or (CH3)2CH-(C=O)-, and R4 is hydrogen.

[0243] In one embodiment of any of the above, R2 is methyl, R3 is acetyl, and R4 is hydrogen.

[0244] In one embodiment of any of the above, the compound is selected from the group consisting of:

[0245] [ka]

[0246] [ka]

[0247] [ka]

[0248] [ka]

[0249] [ka] During the ceremony,

[0250] [ka] is the bond to the linker.

[0251] In one aspect, the present disclosure provides an antibody drug conjugate having a structure according to formula (XXII):

[0252] [ka] During the ceremony, BA is an antibody or antigen-binding fragment thereof, L is a linker, SP is a spacer group selected from:

[0253] [ka] Here, the symbol

[0254] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbon, and fluorenylmethyloxycarbonyl (F MOC ) and tert-butyloxycarbonyl (B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; Y is C or N; R' and R" are independently hydrogen and C when present. 1-6 alkyl, and X is selected from -O-, -S-, and -NR * is selected from.

[0255] In one embodiment, the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof, and comprises (a) a complementarity-determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 9, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 9.

[0256] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 46, 62, 102, and 294; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 48, 64, 104, and 296; Includes.

[0257] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising the amino acid sequence of SEQ ID NO: 52; and (ii) an HCDR2 domain comprising the amino acid sequence of SEQ ID NO: 54; and (iii) an HCDR3 domain comprising the amino acid sequence of SEQ ID NO: 56; and (iv) an LCDR1 domain comprising the amino acid sequence of SEQ ID NO: 60; and (v) an LCDR2 domain comprising the amino acid sequence of SEQ ID NO: 62; and (vi) an LCDR3 domain comprising the amino acid sequence of SEQ ID NO: 64; Includes.

[0258] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0259] In one embodiment, an anti-WTA antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 2A, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 2A.

[0260] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 470, 476, 482, and 488; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 471, 477, 483, and 489; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 472, 478, 484, and 490; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 467, 473, 479, and 485; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 468, 474, 480, and 486; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 469, 475, 481, and 487; May include:

[0261] In one embodiment, an anti-WTA antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 2B, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 2B.

[0262] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, and 574; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, and 575; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576, and 584; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565, and 571; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566, and 572; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567, and 573; May include:

[0263] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation (EU numbering) in the light chain.

[0264] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof is derived from antibody 4497 ​​described in U.S. Patent Application Publication No. 20140356375, which is incorporated herein by reference in its entirety. In one embodiment, the anti-WTA antibody is derived from antibody 4497 ​​and further comprises a V205C mutation in the light chain.

[0265] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 of SEQ ID NOs: 568-569-570-565-566-567.

[0266] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 586 and three light chain complementarity determining regions (LCDR1, LCDR2, LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 585.

[0267] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO:586 and the LCVR amino acid sequence of SEQ ID NO:585.

[0268] In some embodiments, the anti-WTA antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 602 and the light chain amino acid sequence of SEQ ID NO: 587 or 589. In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation in the light chain.

[0269] In one embodiment, an anti-Protein A antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 3A, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 3A.

[0270] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 632, 652, and 672; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 634, 654, and 674; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 636, 656, and 676; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 640, 660, and 680; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 642 and 662; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 644, 664, and 683.

[0271] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises H435R and Y436F mutations (EU numbering) in the heavy chain Fc.

[0272] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 630 and three light chain complementarity determining regions (LCDR1, LCDR2, LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 638. In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises a series of six CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) comprising SEQ ID NOs: 632-634-636-640-642-644.

[0273] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO:630 and the LCVR amino acid sequence of SEQ ID NO:638.

[0274] In one embodiment, the anti-Protein A antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 666 and the light chain amino acid sequence of SEQ ID NO: 668. In one embodiment, the anti-Protein A antibody further comprises H435R and Y436F mutations (EU numbering) in the heavy chain Fc. In one embodiment, the anti-Protein A antibody further comprises a C103S mutation in the light chain. In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof is conjugated to a compound of the present disclosure at position 103 of the light chain.

[0275] In various embodiments, the antibody or antigen-binding fragment thereof comprises a C103S mutation in the light chain.

[0276] In various embodiments, the antibody or antigen-binding fragment thereof is conjugated to a compound of the present disclosure at position 103 of the light chain.

[0277] In one embodiment, L is a linker having the formula:

[0278] [ka] wherein RG is selected from maleimide, N-hydroxysuccinimide, or succinimide; and SP 1 and SP 2 is independently non-existent or

[0279] [ka] C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH-, -(CH) u -C(O)-NH-, (-CH2-CH2-O) e , -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v -, ... AA 2-4 is a peptide unit containing 2 to 4 amino acids, and PEG is a polyethylene glycol chain containing 1 to 30 polyethylene glycol residues.

[0280] In one embodiment, AA 2-4 is a dipeptide selected from valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, glycine-valine, alanine-glycine, or alanine-alanine.

[0281] In one embodiment, AA 2-4 is valine-citrulline.

[0282] In one embodiment, the SP is

[0283] [ka] and R' and R" are C 1-6 It is alkyl.

[0284] In one embodiment, the SP is

[0285] [ka] where R' and R" are each methyl.

[0286] In one embodiment, the SP 1 and SP 2 are respectively,

[0287] [ka] be.

[0288] In one embodiment, the PEG comprises 8 polyethylene glycol units.

[0289] In one embodiment, BA is an antibody or antigen-binding fragment thereof and L is a linker having the formula:

[0290] [ka] During the ceremony, RG is selected from maleimide or succinimide; SP 1 and SP 2 are respectively,

[0291] [ka] and AA 2-4 is valine-citrulline, PEG is a polyethylene glycol chain containing eight polyethylene glycol residues, SP is

[0292] [ka] wherein R' and R" are each methyl; and X is -O-.

[0293] In one embodiment, the antibody drug conjugate has the formula:

[0294] [ka] wherein BA is an antibody or antigen-binding fragment thereof.

[0295] In another aspect, the disclosure provides an antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof is conjugated directly or via a linker or linker-spacer to a payload having a structure selected from the group consisting of:

[0296] [ka]

[0297] [ka]

[0298] [ka]

[0299] [ka]

[0300] [ka]

[0301] In one embodiment, the payload has a structure selected from the following:

[0302] [ka]

[0303] In one embodiment, the payload is conjugated via a linker, wherein the linker has the structure:

[0304] [ka] During the ceremony, RG is selected from maleimide or succinimide; SP 1 and SP 2 is independently non-existent or

[0305] [ka] C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH-, -(CH) u -C(O)-NH-, (-CH2-CH2-O) e , -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v -, ... AA 2-4 is a peptide unit containing 2 to 4 amino acids, and PEG is a polyethylene glycol chain containing 1 to 30 polyethylene glycol residues.

[0306] In one embodiment, AA 2-4 is a dipeptide selected from valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, or glycine-valine.

[0307] In one embodiment, AA 2-4 is valine-citrulline.

[0308] In one embodiment, the SP is

[0309] [ka] and R' and R" are C 1-6 It is alkyl.

[0310] In one embodiment, the SP is

[0311] [ka] where R' and R" are each methyl.

[0312] In one embodiment, the SP 1 and SP 2 are respectively,

[0313] [ka] is.

[0314] In one embodiment, the PEG comprises 8 polyethylene glycol units.

[0315] In one embodiment, the payload is conjugated via a linker, wherein the linker has the structure:

[0316] [ka]

[0317] In one embodiment, the payload is conjugated via a linker, and the linker payload has the structure:

[0318] [ka] During the ceremony,

[0319] [ka] is the binding to an antibody or antigen-binding fragment thereof.

[0320] In one embodiment, the payload is conjugated via a linker, and the linker payload has the structure:

[0321] [ka] During the ceremony,

[0322] [ka] is the binding to an antibody or antigen-binding fragment thereof.

[0323] In one embodiment, the antibody or antigen-binding fragment thereof that binds to macrophage scavenger receptor 1 (MSR1) comprises (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 9, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 9.

[0324] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 46, 62, 102, and 294; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 48, 64, 104, and 296; Includes.

[0325] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising the amino acid sequence of SEQ ID NO: 52; and (ii) an HCDR2 domain comprising the amino acid sequence of SEQ ID NO: 54; and (iii) an HCDR3 domain comprising the amino acid sequence of SEQ ID NO: 56; and (iv) an LCDR1 domain comprising the amino acid sequence of SEQ ID NO: 60; and (v) an LCDR2 domain comprising the amino acid sequence of SEQ ID NO: 62; and (vi) an LCDR3 domain comprising the amino acid sequence of SEQ ID NO: 64; Includes.

[0326] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0327] In one embodiment, an anti-WTA antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 2A, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 2A.

[0328] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 470, 476, 482, and 488; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 471, 477, 483, and 489; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 472, 478, 484, and 490; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 467, 473, 479, and 485; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 468, 474, 480, and 486; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 469, 475, 481, and 487; May include:

[0329] In one embodiment, an anti-WTA antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 2B, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 2B.

[0330] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, and 574; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, and 575; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576, and 584; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565, and 571; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566, and 572; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567, and 573; May include:

[0331] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation (EU numbering) in the light chain.

[0332] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof is derived from antibody 4497 ​​described in U.S. Patent Application Publication No. 20140356375, which is incorporated herein by reference in its entirety. In one embodiment, the anti-WTA antibody is derived from antibody 4497 ​​and further comprises a V205C mutation in the light chain.

[0333] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 of SEQ ID NOs: 568-569-570-565-566-567.

[0334] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 586 and three light chain complementarity determining regions (LCDR1, LCDR2, LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 585.

[0335] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO:586 and the LCVR amino acid sequence of SEQ ID NO:585.

[0336] In some embodiments, the anti-WTA antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 602 and the light chain amino acid sequence of SEQ ID NO: 587 or 589. In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation in the light chain.

[0337] In one embodiment, an anti-Protein A antibody or antigen-binding fragment thereof may comprise (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence set forth in Table 3A, and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence set forth in Table 3A.

[0338] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 632, 652, and 672; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 634, 654, and 674; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 636, 656, and 676; (iv) an LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 640, 660, and 680; (v) an LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 642 and 662; (vi) an LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 644, 664, and 683; May include:

[0339] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises H435R and Y436F mutations (EU numbering) in the heavy chain Fc.

[0340] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises H435R and Y436F mutations (EU numbering) in the heavy chain Fc.

[0341] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 630 and three light chain complementarity determining regions (LCDR1, LCDR2, LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 638. In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises a series of six CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) comprising SEQ ID NOs: 632-634-636-640-642-644.

[0342] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO:630 and the LCVR amino acid sequence of SEQ ID NO:638.

[0343] In one embodiment, the anti-Protein A antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 666 and the light chain amino acid sequence of SEQ ID NO: 668. In one embodiment, the anti-Protein A antibody further comprises H435R and Y436F mutations (EU numbering) in the heavy chain Fc. In one embodiment, the anti-Protein A antibody further comprises a C103S mutation in the light chain. In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof is conjugated to a compound of the present disclosure at position 103 of the light chain.

[0344] In various embodiments, the antibody or antigen-binding fragment thereof comprises a C103S mutation in the light chain.

[0345] In various embodiments, the antibody or antigen-binding fragment thereof is conjugated to a compound of the present disclosure at position 103 of the light chain.

[0346] In one aspect, the disclosure provides a method of preventing or inhibiting bacterial growth, the method comprising administering an effective amount of an antibody drug conjugate described herein.

[0347] In one embodiment, the bacterium is a gram-positive bacterium.

[0348] In one embodiment, the bacterium is penicillin-resistant.

[0349] In one embodiment, the bacterium is Staphylococcus aureus.

[0350] In one embodiment, the bacteria is selected from methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and methicillin-sensitive Staphylococcus aureus (MSSA).

[0351] In one aspect, the present disclosure provides a method of treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of an antibody drug conjugate described herein.

[0352] In one embodiment, the bacterial infection is a gram-positive infection.

[0353] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[0354] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[0355] In one embodiment, the bacterial infection is selected from a methicillin-resistant Staphylococcus aureus (MRSA) infection, a vancomycin-resistant Staphylococcus aureus (VRSA) infection, and a methicillin-sensitive Staphylococcus aureus (MSSA) infection.

[0356] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[0357] In one embodiment, the subject is a human.

[0358] In one embodiment, the method further comprises administering a second therapeutic agent.

[0359] In one embodiment, the second therapeutic agent is a second antibiotic.

[0360] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[0361] In one embodiment, the second antibiotic is selected from an aminoglycoside, a beta-lactam, a macrolide, a cyclic peptide, a tetracycline, a fluoroquinoline, a fluoroquinolone, and an oxazolidinone.

[0362] In one embodiment, the second antibiotic is selected from clindamycin, novobiocin, retapamulin, daptomycin, sitafloxacin, teicoplanin, triclosan, naphthyridone, radezolid, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin.

[0363] In one embodiment, the antibody drug conjugate is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[0364] In yet another aspect, the present disclosure provides a method of preventing or treating cellulitis, bacteremia, skin necrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boils, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, post-burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, septic arthritis, mastitis, prosthetic joint-related infection, catheter-related infection, or implant-related infection in a subject, the method comprising administering to the subject an effective amount of a compound, antibody drug conjugate, or pharmaceutical composition described herein.

[0365] These and other aspects of the present disclosure will become apparent to those skilled in the art upon reading the following detailed description of the disclosure, including the appended claims. [Brief explanation of the drawings]

[0366] [Figure 1] 1 is a plot showing the results of a Staphylococcus aureus growth inhibition assay performed with rifamycin analogs of the present disclosure. [Figure 2] 1 is a bar graph showing the results of a Staphylococcus aureus intracellular killing assay performed with rifamycin analogs of the present disclosure. [Figure 3] 1 is a plot showing the results of a Staphylococcus aureus intracellular killing growth assay performed with rifamycin analogs of the present disclosure. [Figure 4] 1 is an overview of a 4-day Staphylococcus aureus infection model. [Figure 5] 1 is a plot showing colony forming units of anti-Staphylococcus aureus ADCs of the disclosure in an intracellular killing assay using THP cells. [Figure 6]1 depicts the mean S. aureus kidney burden in mice administered 2 mg / kg of isotype control and anti-WTA Ab-antibiotic ncADC (antibody drug conjugate) of the present disclosure in combination with vancomycin. [Figure 7] 1 depicts the mean S. aureus kidney burden in mice administered 2 mg / kg of isotype control and anti-Protein A Ab-antibiotic ncADC of the present disclosure in combination with vancomycin. [Figure 8] 1 depicts the mean S. aureus kidney burden in mice administered 5 mg / kg of isotype control and anti-WTA Ab-antibiotic ncADCs of the present disclosure in combination with vancomycin. DETAILED DESCRIPTION OF THE INVENTION

[0367] Detailed embodiments of the present disclosure are disclosed herein. However, it should be understood that the disclosed embodiments are merely exemplary of the present disclosure, which may be embodied in various forms. In addition, each example given in connection with various embodiments of the present disclosure is intended as illustrative and not limiting. Therefore, specific structural and functional details disclosed herein should not be construed as limiting, but merely as a representative basis for teaching those skilled in the art how to utilize the present disclosure in various ways.

[0368] definition

[0369] Unless otherwise defined, 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.

[0370] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "method" includes one or more of the methods, and / or steps described herein and / or that will become apparent to those skilled in the art upon reading this disclosure.

[0371] The term "treating" or "treatment" with respect to a condition, disorder, or disease includes (1) preventing, delaying, or reducing the occurrence and / or likelihood of at least one clinical or subclinical symptom of said condition, disorder, or disease in a subject suffering from or prone to suffering from said condition, disorder, or disease but who has not yet experienced or displayed clinical or subclinical symptoms of said condition, disorder, or disease; (2) inhibiting said condition, disorder, or disease, i.e., arresting, reducing, or delaying the disease or recurrence or progression of at least one clinical or subclinical symptom thereof; and / or (3) palliating the disease, i.e., causing regression of said condition, disorder, or disease or at least one of its clinical or subclinical symptoms. The benefit to the treated subject will be statistically significant or at least perceptible to the patient or physician.

[0372] As used herein, "subject," "patient," "individual," or "animal" refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.), and experimental animal models (e.g., mice, rats) with a disease. In one embodiment, the subject is a human.

[0373] As used herein, the term "effective" as used in reference to dosage or amount refers to an amount of a compound or pharmaceutical composition sufficient to produce the desired activity upon administration to a subject in need. It should be noted that when administered in combination with active ingredients, the effective amount of the combination may or may not include the amount of each ingredient that was effective when administered individually. The exact amount required will vary from subject to subject, depending on the subject's sex, age, general condition, the severity of the disease being treated, the particular drug utilized, the mode of administration, etc.

[0374] The phrase "pharmaceutically acceptable," as used in connection with the compositions of the present disclosure, refers to molecular entities and other components of the composition that are physically tolerated and that do not normally produce adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency, listed in the United States Pharmacopoeia, or generally recognized for use in mammals, more specifically, humans.

[0375] As used herein, the phrase "therapeutically effective amount" refers to an amount that, when administered, produces a desired effect. The precise amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0376] Ranges may be expressed herein as from "about" or "approximately" one particular value to "about" or "approximately" another particular value. When such a range is expressed, another embodiment includes from the one particular value to the other particular value.

[0377] "Comprising," "containing," or "including" means that at least the specified compound, element, particle, or method step is present in a composition, article, or method, but does not exclude other compounds, materials, particles, or method steps, even if such other compounds, materials, particles, or method steps have the same function as the specified one.

[0378] Compounds of the present disclosure include those described throughout the specification and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B., and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006.

[0379] The term "hydrocarbon" is used herein to encompass hydrocarbon radicals (otherwise referred to as "groups"), including carbon and hydrogen, as well as derivatives where one or more carbons are substituted with heteroatoms such as oxygen, nitrogen, sulfur, and phosphorus. The hydrocarbons of this disclosure are optionally substituted with oxygen, nitrogen, sulfur, and phosphorus containing groups, or, without limitation, with halogens. The term hydrocarbon encompasses straight-chain, branched-chain, cyclic, or polycyclic aliphatic groups, as well as aromatic and heteroaromatic groups, as detailed below.

[0380] The term "optionally substituted" has the same meaning as "the substituted element further comprises 0 to n" optional elements, where n is an integer, typically 0 to 20, 0 to 10, or 1 to 3. For example, when an aliphatic hydrocarbon optionally comprises one or more heteroatoms, the term has the same meaning as "the aliphatic hydrocarbon further comprises 0 to 20 heteroatoms."

[0381] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (unbranched), branched-chain, substituted, or unsubstituted hydrocarbon chain that is fully saturated, unsaturated, contains one or more units of fully saturated monocyclic, bicyclic, or tricyclic hydrocarbon, contains one or more units of unsaturation but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl"), or has a single point of attachment to the rest of the molecule, and combinations thereof. In some embodiments, aliphatic groups include combinations (hybrids) of straight-chain and cyclic aliphatic hydrocarbons. In some embodiments, aliphatic groups include combinations of straight-chain and cyclic aliphatic hydrocarbons. Unless otherwise specified, aliphatic groups contain 1-30 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and combinations / hybrids of (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or alkenyl(cycloalkyl), etc. Simple aliphatic hydrocarbons include methyl, ethyl, propyl, butyl, t-butyl, n-butyl, pentyl, etc.

[0382] As used herein, the terms "alicyclic," "cycloaliphatic," "carbocyclic," "alicyclic," and "cycloaliphatic" refer to saturated or partially unsaturated cycloaliphatic monocyclic, bicyclic, or polycyclic ring systems as described herein having 3 to 14 members, where the aliphatic ring systems are optionally substituted as described above and herein. Alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, cycloalkyls have 3 to 6 carbons. Aliphatic ring structures further include aliphatic rings fused to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring. In some embodiments, the aliphatic cyclic group is bicyclic. In some embodiments, the carbocyclic group is tricyclic. In some embodiments, the aliphatic cyclic group is polycyclic. In some embodiments, the aliphatic polycyclic group is a spirocyclic structure, which represents a twisted structure (ring system) of two or more rings, where two or three rings are joined together by a common atom. In other embodiments, the aliphatic polycyclic group is a fused bicyclic structure, where two rings share two adjacent atoms, i.e., the rings share one covalent bond, and so-called bridgehead atoms are directly connected (e.g., α-thujene and decalin). In some embodiments, the aliphatic polycyclic structure is a bridged bicyclic structure, where, for example, two rings share three or more atoms, and a bridge containing at least one atom separates the two bridgehead atoms. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered as a pair of cyclopentanes, each sharing three of its five carbon atoms.In some embodiments, an "aliphatic cyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon, C6-C6, that is fully saturated or contains one or more units of unsaturation but is not aromatic and has one point of attachment to the rest of the molecule. 12 Bicyclic hydrocarbons, or C6-C, which are fully saturated or contain one or more units of unsaturation but are not aromatic and have one point of attachment to the rest of the molecule 12 Refers to bicyclic hydrocarbons.

[0383] As used herein, the term "alkyl" is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In some embodiments, the backbone of a straight-chain or branched-chain alkyl group may contain from about 1 to 20 carbon atoms (e.g., C1-C5 for a straight chain). 20 , C2-C for branched chains 20 ), and alternatively about 1 to 10 carbon atoms, or about 1 to 6 carbon atoms. In some embodiments, the ring structure of a cycloalkyl ring has about 3 to 10 carbon atoms, and alternatively about 5, 6, or 7 carbons, where the ring is monocyclic or bicyclic. In some embodiments, an alkyl group can be a lower alkyl group, where the lower alkyl group contains 1 to 4 carbon atoms (e.g., C1-C4 for a straight chain lower alkyl).

[0384] As used herein, the term "alkenyl" refers to an alkyl group, as defined herein, having one or more double bonds.

[0385] As used herein, the term "alkynyl" refers to an alkyl group, as defined herein, having one or more triple bonds.

[0386] The term "heteroalkyl" is given its ordinary meaning in the art and refers to an alkyl group, as described herein, in which one or more carbon atoms are replaced with a heteroatom (e.g., halogen, oxygen, nitrogen, sulfur, etc.). Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0387] As used herein, "aromatic" refers to a monocyclic or polycyclic aromatic or heteroaromatic ring having 5 to 20 ring atoms and optionally 1 to 20 heteroatom substituents. In some embodiments, an aromatic group may optionally have 1 to 10 heteroatom substituents. In some embodiments, an aromatic group may optionally have 1 to 5 heteroatom substituents. In some embodiments, an aromatic group is a monocyclic or polycyclic aromatic ring such as cyclopentadienyl, phenyl, naphthyl, or anthracenyl. In some embodiments, an aromatic group is a monocyclic or polycyclic aromatic ring having 5 to 10 ring atoms. In some embodiments, an aromatic group is a monocyclic aromatic ring containing 5 to 6 carbon atoms, such as phenyl and cyclopentadienyl. In one particular embodiment, the aromatic group is a phenyl group.

[0388] The term "aryl," when used alone or as part of a larger moiety, as in "aralkoxy" or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the ring system is aromatic and each ring contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyi, and the like, which may bear one or more substituents. As used herein, included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl.

[0389] The terms "heteroaromatic hydrocarbon," "heteroaryl," and "heteroar-," when used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms (monocyclic or bicyclic), in some embodiments 5, 6, 9, or 10 ring atoms. In some embodiments, such rings have 6, 10, or 14 π-electrons shared in the cyclic array and further have 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaromatic hydrocarbon or heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, heteroaryl is a heterobiaryl group such as bipyridyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the aromatic heterocycle. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic, bicyclic, tricyclic, tetracyclic, and / or other polycyclic rings.The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic ring," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, in which the alkyl and heteroaryl portions independently are optionally substituted.

[0390] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen.

[0391] A heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and refer to a group in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups may be monocyclic, bicyclic, tricyclic, tetracyclic, and / or other polycyclic rings. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl moieties independently are optionally substituted.

[0392] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0393] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle).

[0394] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation. The term "halogen" means F, Cl, Br, or I. The term "halide" refers to a halogen radical or substituent, i.e., -F, -Cl, -Br, or -I. As used herein, "haloalkyl" refers to an alkyl as defined above, where the alkyl contains at least one substituent selected from a halogen, e.g., fluorine (F), chlorine (Cl), bromine (Br), iodine (I). Examples of haloalkyl include, but are not limited to, -CF3, -CH2CF3, -CCl2F, and -CCl3.

[0395] As used herein, the term "protecting group" refers to a group introduced into a molecule by chemical modification of a functional group, such as an amino or alcohol, to obtain chemoselectivity in a subsequent chemical reaction. In one non-limiting embodiment, the protecting group may include 1-chloroethylcarbonyl (ACE), acetoyl, benzyl (Bn), benzyloxycarbonyl (CBz), formyl, methylcarbonyl, trifluoroacetyl, t-butoxycarbonyl (Boc), and fluorenylmethyloxycarbonyl (Fmoc). In other non-limiting embodiments, protecting groups include arbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) groups, tosyl (Ts), Troc (trichloroethyl chloroformate), sulfonamides such as nosyl and Nps. In further non-limiting embodiments, protecting groups include β-methoxyethoxymethyl ether (MEM), dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT), methoxymethyl ether (MOM), methoxytrityl[(4-methoxyphenyl)diphenylmethyl] (MMT), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), trityl (triphenylmethyl, Tr), silyl ether (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ether, TBDMS, TOM, methyl ether, and ethoxyethyl ether (EE).

[0396] As used herein, the term "O amino acid" or "HO amino acid" refers to an amino acid in which the native amino group at the N-terminus of the amino acid or amino acid sequence is replaced with an oxygen group or a hydroxyl group, respectively. For example, "O-XXXX" or "HO-XXXX" is intended to indicate an amino acid sequence (XXXX) in which the native amino group at the N-terminus is replaced with an oxygen group or a hydroxyl group, respectively (e.g.,

[0397] [ka] where each R is an amino acid side chain. Similarly, the term "O amino acid residue" or "HO amino acid residue" refers to the chemical moiety in a compound that remains after a chemical reaction. For example, "O amino acid residue" or "HO amino acid residue" refers to the product of an amide coupling or peptide coupling in which an O amino acid or an HO amino acid is coupled to an appropriate coupling partner. Here, for example, a water molecule is expelled after the amide coupling or peptide coupling of the O amino acid or the HO amino acid, thereby resulting in a product incorporating the O amino acid residue or the HO amino acid residue therein.

[0398] The designation of an amino acid or amino acid residue without specifying stereochemistry is intended to encompass the L-form of the amino acid, the D-form of the amino acid, or racemic mixtures thereof.

[0399] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure is substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is not substantially modified when exposed to conditions that permit production, detection, and, in some embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0400] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric mixtures of the present compounds are within the scope of the disclosure.

[0401] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0402] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, replacement of hydrogen by deuterium or tritium; 11 C. 13 C, or 14 Substitution of carbon by C-rich carbon, 17 Or 18 Replacement of oxygen with O-rich oxygen, or15 Compounds having the present structures, except for the replacement of a nitrogen with an N-rich nitrogen, are within the scope of this disclosure.

[0403] It should also be understood that a reference to one or more method steps does not exclude the presence of additional method steps or intervening method steps between the explicitly identified steps. Similarly, it should also be understood that a reference to one or more components in a device or system does not exclude the presence of additional components or intervening components between the explicitly identified components.

[0404] Unless otherwise specified, all crystalline forms of the disclosed compounds and their salts are also within the scope of the present disclosure. The disclosed compounds may be isolated in various amorphous and crystalline polymorphic forms, including, but not limited to, anhydrous, hydrated, unsolvated, or solvated amorphous and crystalline polymorphic forms. Examples of hydrates include hemihydrates, monohydrates, dihydrates, etc. In some embodiments, the disclosed compounds are anhydrous and unsolvated. "Anhydrous" means that the crystalline form of the compound is substantially free of bound water in the crystal lattice structure, i.e., the compound does not form a crystalline hydrate.

[0405] As used herein, "crystalline form" is intended to refer to a particular lattice configuration of a crystalline substance. Different crystalline forms (polymorphs) of the same substance typically have different crystal lattices (e.g., unit cells) due to the different physical properties characteristic of each crystalline form. In some instances, the different lattice configurations contain different amounts of water or solvent. Different crystalline lattices can be identified by solid-state characterization methods such as X-ray powder diffraction (PXRD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and solid-state NMR, further aid in identifying crystalline forms, as well as determining stability and solvent / water content.

[0406] Crystalline forms of a substance include both solvated (e.g., hydrated) and unsolvated (e.g., anhydrous) forms. Hydrated forms are crystalline forms that contain water in the crystal lattice. Hydrated forms may be stoichiometric hydrates, where water is present in the lattice at a specific water / molecule ratio for hemihydrates, monohydrates, dihydrates, etc. Hydrated forms may also be non-stoichiometric, where the water content varies and is dependent on external conditions such as humidity.

[0407] In some embodiments, the compounds of the present disclosure are substantially isolated. "Substantially isolated" means that a particular compound is at least partially isolated from impurities. For example, in some embodiments, the compounds of the present disclosure contain less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% impurities. Impurities generally include anything that is not a substantially isolated compound, such as other crystalline forms and other substances.

[0408] As used herein, the term "antibiotic" (abx or Abx) includes any molecule that specifically inhibits the growth of or kills microorganisms, such as bacteria, but is not lethal to the host at the concentrations and intervals at which it is administered. In certain embodiments, the antibiotic is non-toxic to the host at the concentrations and intervals at which it is administered. Antibiotics that are effective against bacteria can be broadly classified as either bactericidal (killing directly) or bacteriostatic (preventing division). Antibacterial antibiotics can be further subclassified as narrow-spectrum or broad-spectrum. Broad-spectrum antibiotics are antibiotics that are effective against a variety of bacteria, including both gram-positive and gram-negative bacteria, as opposed to narrow-spectrum antibiotics, which are effective against a smaller range or specific family of bacteria. Examples of antibiotics include aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromycin, ansamycins such as geldanamycin and herbimycin, carbacephems such as loracarbef, carbapenems such as ertapenem, doripenem, imipenem / cleastatin, meropenem, cephalosporins (first generation) such as cefadroxil, cefazolin, cephalothin, cephalexin, cephalosporins (second generation) such as cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cephalosporins (third generation) such as cefixime, cefdinir, cefditoren, cefoperazone. , cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cephalosporins (fourth generation) such as cefepime, cephalosporins (fifth generation) such as ceftobiprole, glycopeptides such as teicoplanin, vancomycin, macrolides such as axithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, monobactams such as aztreonam, penicillins such as amoxicillin, ampicillin, axlocillin, carbenicillin, cloxacillin, dicloxacillin,Flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, antibiotic polypeptides such as bacitracin, colistin, polymyxin B, quinolones such as ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, remefloxacin, moxifloxacin, norfloxacin, orfloxacin, trovafloxacin, sulfonamides such as mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim ... Toprim-sulfamethoxazole (TMP-SMX), tetracyclines such as demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, and other antibiotics such as arspenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampin / rifampicin, or timidazole.

[0409] The term "methicillin-resistant Staphylococcus aureus" (MRSA), also known as multidrug-resistant Staphylococcus aureus or oxacillin-resistant Staphylococcus aureus (ORSA), refers to any strain of Staphylococcus aureus that is resistant to beta-lactam antibiotics, including penicillins (e.g., methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and cephalosporins. "Methicillin-susceptible Staphylococcus aureus" (MSSA) refers to any strain of Staphylococcus aureus that is susceptible to beta-lactam antibiotics.

[0410] The term "minimum inhibitory concentration" ("MIC") refers to the lowest concentration of an antimicrobial agent that inhibits visible growth of a microorganism after overnight incubation. Assays for determining the MIC are known. One method is described in the Examples below.

[0411] The drug-to-antibody ratio (DAR) is the average number of drugs conjugated to an antibody or antigen-binding fragment, which has important effects on the efficacy, potency, and pharmacokinetics of an ADC. In various embodiments, the DAR is derived from 1, 2, 3, 4, 5, 6, 7, or 8 drug molecules per antibody. In some embodiments, the DAR is 1 to 8. In some embodiments, the DAR is 1 to 6. In certain embodiments, the DAR is 2 to 4. In some cases, the DAR is 2 to 3. In some cases, the DAR is 0.5 to 3.5. In some embodiments, the DAR is about 1, about 1.5, about 2, about 2.5, about 3, or about 3.5.

[0412] As used herein, the terms "MSR1," "hMSR1," and the like refer to a human single-pass trimeric type II transmembrane glycoprotein pattern recognition receptor comprising (i) the amino acid sequence set forth in NCBI Accession No. NP_002436.1, (ii) the amino acid sequence set forth in NCBI Accession No. NP_619729.1, and / or (iii) the amino acid sequence set forth in NCBI Accession No. NP_619730.1, which represent various species and isoforms of class A macrophage scavenger receptors. The term "MSR1" encompasses both monomeric and multimeric MSR1 molecules. As used herein, the term "monomeric human MSR1" refers to an MSR1 protein or portion thereof that does not contain or possess a multimerization domain and exists under normal conditions as a single MSR1 molecule without direct physical association with another MSR1 molecule. An exemplary monomeric MSR1 molecule is the molecule designated herein as "His-hMSR1," which comprises the amino acid sequence of SEQ ID NO: 393 (see, eg, Example 25 herein).

[0413] All references herein to proteins, polypeptides, and protein fragments are intended to refer to the respective human protein, polypeptide, or protein fragment unless specifically identified as being from a non-human species. Thus, the term "MSR1" refers to human MSR1 unless specifically identified as being from a non-human species, e.g., "mouse MSR1," "monkey MSR1," etc.

[0414] As used herein, the term "cell surface-expressed MSR1" refers to one or more MSR1 proteins, or extracellular domains thereof, expressed on the cell surface in vitro or in vivo such that at least a portion of the MSR1 protein is exposed to the extracellular surface of the cell membrane and accessible to the antigen-binding portion of an antibody. "Cell surface-expressed MSR1" may include or consist of an MSR1 protein expressed on the surface of a cell that normally expresses the MSR1 protein. Alternatively, "cell surface-expressed MSR1" may include or consist of an MSR1 protein expressed on the surface of a cell that does not normally express human MSR1 on its surface but has been artificially engineered to express MSR1 on its surface.

[0415] As used herein, the term "anti-MSR1 antibody" includes monovalent antibodies with a single specificity, as well as bispecific antibodies comprising a first arm that binds to MSR1 and a second arm that binds to a second (target) antigen, wherein the anti-MSR1 arm comprises any of the HCVR / LCVR or CDR sequences listed in Table 9. The term "anti-MSR1 antibody" also includes antibody-drug conjugates (ADCs), which comprise an anti-MSR1 antibody, or an antigen-binding portion thereof, conjugated to a drug or therapeutic agent. The term "anti-MSR1 antibody" further includes antibody-radionuclide conjugates (ARCs), which comprise an anti-MSR1 antibody, or an antigen-binding portion thereof, conjugated to a radionuclide.

[0416] The term "wall teichoic acid" (WTA) refers to an anionic glycopolymer covalently attached to peptidoglycan via a phosphodiester bond to the C6 hydroxyl of the N-acetylmuramic acid sugar. While the exact chemical structure may vary between organisms, in some embodiments, WTA is a ribitol teichoic acid with one repeating unit at position 2, a 1,5-phosphodiester bond repeating unit of D-ribitol and D-alanyl, and a glycosyl substituent at position 4. The glycosyl group may be N-acetylglucosaminyl α or β, as present in Staphylococcus aureus. The hydroxyl on the alditol / sugar alcohol phosphate repeat may be substituted with cationic D-alanine esters and monosaccharides, such as N-acetylglucosamine. The hydroxyl substituent may include D-alanyl, and α or β GlcNHAc. In one specific embodiment, WTA comprises a compound of the following formula:

[0417] [ka]

[0418] where the wavy lines represent repeating binding units or sites of Polyalditol-P or peptidoglycan, X is D-alanyl or --H, and Y is α-GlcNHAc or β-GlcNHAc.

[0419] [ka]

[0420] As used herein, the term "anti-WTA antibody" refers to any antibody that binds to wall teichoic acid (WTA), whether WTAα or WTAβ. The terms "anti-wall teichoic acid α antibody," "anti-WTAα antibody," "anti-αWTA," or "anti-αGlcNac WTA antibody" are used interchangeably to refer to an antibody that specifically binds to WTAα. Similarly, the terms "anti-wall teichoic acid β antibody," "anti-WTAβ antibody," "anti-βWTA," or "anti-βGlcNac WTA antibody" are used interchangeably to refer to an antibody that specifically binds to WTAβ. The term "anti-WTA antibody" includes monovalent antibodies with a single specificity as well as bispecific antibodies comprising a first arm that binds to WTA (whether WTAα or WTAβ) and a second arm that binds to a second (target) antigen, where the anti-WTA arm comprises any of the HCVR / LCVR or CDR sequences listed in Tables 2A and 2B. The term "anti-WTA antibody" also includes antibody drug conjugates (ADCs), which comprise an anti-WTA antibody or antigen-binding portion thereof conjugated to a drug or therapeutic agent.

[0421] The term "antibody," as used herein, refers to any antigen-binding molecule or molecular complex that contains at least one complementarity-determining region (CDR) that specifically binds to or interacts with a particular antigen (e.g., MSR1, WTA, or Protein A). The term "antibody" includes immunoglobulin molecules that contain four polypeptide chains, two heavy (H) chains, and two light (L) chains, interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain contains a heavy chain variable region (referred to herein as HCVR or V). H The heavy chain constant region is made up of three domains: C H 1. C H 2. C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region contains one domain, C L Includes 1. V H Area and V LThese regions may be further subdivided into regions of hypervariability termed complementarity-determining regions (CDRs), interspersed with more conserved regions termed framework regions (FRs). VH and VL each consist of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of an antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be determined based on parallel analysis of two or more CDRs.

[0422] As used herein, the term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like include any naturally occurring, enzymatically produced, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies may be derived from intact antibody molecules using any suitable standard technique, such as, for example, proteolytic digestion or recombinant genetic engineering techniques, which involve the manipulation and expression of DNA-encoded antibody variable regions and, optionally, constant regions. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA may be sequenced or manipulated chemically or by the use of molecular biology techniques to arrange one or more variable and / or constant regions into the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, and / or delete amino acids.

[0423] Non-limiting examples of antigen-binding fragments include (i) Fab fragments, (ii) F(ab')2 fragments, (iii) Fd fragments, (iv) Fv fragments, (v) single-chain Fv (scFv) molecules, (vi) dAb fragments, and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions (e.g., isolated complementarity-determining regions (CDRs) such as CDR3 peptides) of antibodies or restricted FR3-CDR3-FR4 peptides. Domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed within the term "antigen-binding fragment" as used herein.

[0424] Antigen-binding fragments of antibodies typically contain at least one variable domain, which may be of any size or amino acid composition and which, as a whole, comprises at least one CDR adjacent to or in frame with one or more framework sequences. L V related to domain H For antigen-binding fragments containing domains, V H Domains and V L The domains may be positioned relative to each other in any suitable arrangement. For example, the variable region may be a dimer, with the V H -V H , V H -V L , or V L -V L Alternatively, the antigen-binding fragment of an antibody contains a monomeric V dimer. H Domain or V L In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant region. Exemplary, but non-limiting, configurations of variable and constant regions found in antigen-binding fragments of antibodies of the present disclosure include: (i) a VH -C H 1, (ii) V H -C H 2, (iii) V H -C H 3, (iv) V H -C H 1-C H 2. (v) V H -C H 1-C H 2-C H 3. (vi) V H -C H 2-C H 3, (vii)V H -C L , (viii) V L -C H 1, (ix)V L -C H 2. (x)V L -C H 3. (xi) V L -C H 1-C H 2, (xii)V L -C H 1-C H 2-C H 3, (xiii)V L -C H 2-C H 3, and (xiv) V L -C L In any configuration of variable and constant regions, including any of the exemplary configurations listed above, the variable and constant regions may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible bond between the variable and / or constant regions in a single polypeptide molecule. Additionally, antigen-binding fragments of antibodies of the present disclosure may be linked (e.g., by disulfide bonds) to each other and / or to one or more monomeric V H Or V L The variable domains may comprise homodimers or heterodimers (or other multimers) of any of the above listed variable and constant domain configurations in covalent association with the domains.

[0425] Like intact antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a separate antigen or a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be suitable for use in the context of the antigen-binding fragments of antibodies of the present disclosure, using routine techniques available in the art.

[0426] The antibodies of the present disclosure may function via complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC). "Complement-dependent cytotoxicity" (CDC) refers to the lysis of antigen-expressing cells by the antibodies of the present disclosure in the presence of complement. "Antibody-dependent cellular cytotoxicity" (ADCC) refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing Fc receptors (FcRs), such as natural killer (NK) cells, neutrophils, and macrophages, recognize bound antibodies on target cells, resulting in lysis of the target cells. CDC and ADCC can be measured using assays well known and available in the art (see, e.g., U.S. Patent Nos. 5,500,362 and 5,821,337, and Clynes et al. (1998) Proc. Natl. Acad. Sci. (USA) 95:652-656). The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the antibody isotype can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0427] In certain embodiments, the antibodies disclosed herein are human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), e.g., in the CDRs and particularly the CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0428] The antibodies disclosed herein may, in some embodiments, be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to encompass all human antibodies prepared, expressed, generated, or isolated by recombinant means, including antibodies expressed using a recombinant expression vector transfected into a host cell (described in more detail below), antibodies isolated from a recombinant combinatorial human antibody library (described in more detail below), antibodies isolated from an animal (e.g., a mouse) that carries human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using animals transgenic for human Ig sequences, in vivo somatic mutagenesis) to alter the V and constant regions of the recombinant antibody. H Area and V L The amino acid sequence of the region is human germline V H Arrays and V LThese are sequences that are derived from sequences but may not naturally exist within the human antibody germline repertoire in vivo.

[0429] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable four-chain construct of approximately 150-160 kDa in which the dimers are held together by interchain heavy chain disulfide bonds. In the other form, the dimers are not linked by interchain disulfide bonds, forming a molecule of approximately 75-80 kDa composed of covalently linked light and heavy chains (half antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0430] The frequency of occurrence of the second form among various intact IgG isotypes is due to structural differences associated with, but not limited to, the antibody hinge region isotype. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to the level normally observed using a human IgG1 hinge. The embodiments disclosed herein provide for the modification of the hinge, C ... H 2, or C H The present invention includes antibodies with one or more mutations in the three regions.

[0431] An antibody disclosed herein may be an isolated antibody. As used herein, an "isolated antibody" refers to an antibody that has been identified, separated, and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or tissue or cell in which it naturally resides or is naturally produced, is an "isolated antibody" for purposes of this disclosure. An isolated antibody also includes an in situ antibody within a recombinant cell. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0432] The antibodies disclosed herein may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody is derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. Embodiments include antibodies and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids in one or more framework and / or CDR regions are mutated to the corresponding residue in the germline sequence from which the antibody is derived, to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Starting with the heavy and light chain variable regions disclosed herein, one of skill in the art can readily generate numerous antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, V H and / or V LAll framework and / or CDR residues within a domain are mutated back to the residue found in the original germline sequence from which the antibody is derived. In other embodiments, only specific residues are mutated back to the original germline sequence, e.g., only mutated residues found within the first eight amino acids of FR1 or the last eight amino acids of FR4, or only mutated residues found within CDR1, CDR2, or CDR3. In other embodiments, one or more framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (a germline sequence different from the original germline sequence from which the antibody is derived). Furthermore, antibodies of the present disclosure may contain any combination of two or more germline mutations within framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residue in a particular germline sequence, while other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the embodiments disclosed herein.

[0433] Embodiments further include antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, embodiments include anti-MSR1 antibodies comprising the amino acid sequences of the HCVR, LCVR, and / or CDRs, where the conservative amino acid substitutions are 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., compared to the amino acid sequences of the HCVR, LCVR, and / or CDRs listed in Table 9. As another example, embodiments include anti-WTA antibodies comprising the amino acid sequences of the HCVR, LCVR, and / or CDRs, where the conservative amino acid substitutions are 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., compared to the amino acid sequences of the HCVR, LCVR, and / or CDRs listed in Table 2A or 2B. As yet another example, embodiments include anti-Protein A antibodies comprising the amino acid sequences of HCVRs, LCVRs, and / or CDRs, wherein the conservative amino acid substitutions are 10 or less, 8 or less, 6 or less, 4 or less, etc., compared to the amino acid sequences of the HCVRs, LCVRs, and / or CDRs set forth in Table 3A.

[0434] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as the paratope. An antigen may have more than one epitope; therefore, different antibodies may bind to different regions of the antigen and have different biological effects. Epitopes may be either conformational or linear. Conformational epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are epitopes generated by adjacent amino acid residues in a polypeptide chain. In some situations, epitopes may include monosaccharide, phosphoryl, or sulfonyl moieties on the antigen.

[0435] The terms "substantial identity" or "substantially identical," when referring to a nucleic acid or fragment thereof, mean that, upon appropriate nucleotide insertions or deletions and optimal alignment with another nucleic acid (or its complementary strand), there is nucleotide sequence identity over at least about 95%, more preferably at least about 96%, 97%, 98%, or 99%, of the nucleic acid bases, as measured by well-known sequence identity algorithms such as FASTA, BLAST, or GAP, discussed below. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in some instances, encode a polypeptide comprising the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0436] When applied to polypeptides, the terms "substantial similarity" or "substantially similar" mean that two peptide sequences, when best aligned using the programs GAP or BESTFIT with default gap weights, share at least 95% sequence identity, more preferably at least 98% or 99% sequence identity. Preferably, non-identical residue positions differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is replaced with another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitutions do not substantially alter the functional properties of a protein. When two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or similarity may be adjusted upward to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24:307-331. Examples of groups of amino acids with side chains with similar chemical properties include (1) glycine, alanine, valine, leucine, and isoleucine as aliphatic side chains, (2) serine and threonine as aliphatic hydroxyl side chains, (3) asparagine and glutamine as amide-containing side chains, (4) phenylalanine, tyrosine, and tryptophan as aromatic side chains, (5) lysine, arginine, and histidine as basic side chains, (6) aspartate and glutamate as acidic side chains, and (7) cysteine ​​and methionine as sulfur-containing side chains. Preferred conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-1445. A "moderately conservative" substitution is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0437] Sequence similarity for polypeptides, sometimes referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions. For example, GCG software includes programs such as GAP and BESTFIT, which, when used with default parameters, can determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms, or between wild-type proteins and their mutants. See, for example, "GCG Version 6.1." Polypeptide sequences can also be compared using FASTA, a program in GCG Version 6.1, using default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm for comparing the sequences of the present disclosure to databases containing a large number of sequences from various organisms is the computer program BLAST, specifically BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402.

[0438] As used herein, "O-PEG" n " refers to a monovalent moiety attached through a terminal oxygen atom, where n is 1 to 100. For example, when n is 1, O-PEG n is -O-CH2CH2OH, and when n is 2, O-PEG n is -O-CH2CH2O-CH2CH2OH, and when n is 3, O-PEG n is -O-CH2CH2O-CH2CH2O-CH2CH2OH.

[0439] As used herein, a "binding agent" refers to any molecule, e.g., a protein or antibody, that is capable of binding with specificity to a given binding partner, e.g., an antigen.

[0440] As used herein, "linker" refers to a divalent, trivalent, or multivalent molecule that covalently attaches a binding agent to one or more compounds described herein, such as a payload compound and a hydrophilic group as described herein.

[0441] As used herein, "reactive group" or RG refers to a moiety that includes a portion in its structure that is capable of reacting with other chemical moieties and forming a covalent bond, e.g., reacting with an antibody at its cysteine ​​or lysine residue. Exemplary reactive groups of the present disclosure include, but are not limited to, those that include maleimide, succinimide, N-hydroxysuccinimide (NHS), terminal primary amine, haloacetyl group, isothiocyanate, thiol, alcohol, ketone, aldehyde, acid, ester, hydrazide, and aniline. RG also includes moieties having the following structure:

[0442] [ka] wherein X is —O— or —NH—, and LG is a leaving group such as Br.

[0443] As used herein, "amide synthesis conditions" refers to reaction conditions suitable for achieving the formation of an amide, for example, by reaction of a carboxylic acid, an activated carboxylic acid, or an acyl halide with an amine. In some instances, amide synthesis conditions refer to reaction conditions suitable for achieving the formation of an amide bond between a carboxylic acid and an amine. In some of these instances, the carboxylic acid is first converted to an activated carboxylic acid, and then the activated carboxylic acid is reacted with the amine to form the amide. Suitable conditions for achieving amide formation include those utilizing reagents that effect a reaction between a carboxylic acid and an amine, such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU ... )-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), 2 Examples of suitable fluorochemicals include, but are not limited to, 1-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), and carbonyldiimidazole (CDI).

[0444] In some examples, a carboxylic acid is first converted to an activated carboxylic acid ester, and then the activated carboxylic acid ester is treated with an amine to form an amide bond. In certain embodiments, the carboxylic acid is treated with a reagent that activates the carboxylic acid by deprotonating the carboxylic acid and forming a complex with the deprotonated carboxylic acid as a result of nucleophilic attack by the deprotonated carboxylic acid on the protonated reagent. The activated carboxylic acid ester for a particular carboxylic acid is then more susceptible to nucleophilic attack by the amine than it was before the carboxylic acid was activated. This results in the formation of an amide bond. Therefore, the carboxylic acid is said to be activated. Exemplary reagents include DCC and DIC.

[0445] As used herein, "taurine" refers to the reagent

[0446] [ka] , or group

[0447] [ka] In the formula:

[0448] [ka] indicates the atom at which taurine is bonded to the adjacent group in the formula.

[0449] Compounds of the Disclosure

[0450] In accordance with the foregoing objects and others, the present disclosure provides rifamycin analog compounds, precursors and intermediates thereof, pharmaceutical compositions, and methods for inhibiting bacterial growth and / or treating bacterial infections in subjects in need thereof.

[0451] In one aspect, the disclosure provides a rifamycin analog compound having the structure of formula (A), or a pharmaceutically acceptable salt thereof:

[0452] [ka] During the ceremony, X is -O- and -NR * - selected from Za and Zb are independently hydrogen, -Cl, -Br, -OR1, and -R N wherein at least one of Za or Zb is not hydrogen; and wherein R1 is hydrogen, R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R *)2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0453] [ka] is selected from, where the symbol

[0454] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and alkyl groups such as F MOC and B OC or R′ and R″ together form an aliphatic cyclic structure, such as an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbons, and -(C=O)-R* each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0455] In one aspect, the disclosure provides a rifamycin analog compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0456] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R* , -SO2N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0457] [ka] is selected from, where the symbol

[0458] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 hydrocarbons, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R *, -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0459] In one aspect, the disclosure provides a rifamycin analog compound having the structure of formula (I'), or a pharmaceutically acceptable salt thereof:

[0460] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0461] [ka] is selected from, where the symbol

[0462] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R *, -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0463] In one embodiment of a compound of Formula (A), (I), or (I′), X is —O—, R1 is an aliphatic C1-C3 hydrocarbon, R2 is a methyl group, R3 is Ac(—(C═O)—CH3), R4 is hydrogen, and R a is hydrogen.

[0464] In one embodiment of a compound of Formula (A), (I), or (I′), X is —O—, R1 is a benzyl group, R2 is a methyl group, R3 is Ac(—(C═O)—CH3), R4 is hydrogen, and R a is hydrogen and R b is hydrogen.

[0465] In one embodiment of a compound of Formula (A), (I), or (I′), X is —O—, R1 is an aliphatic C1-C8 hydrocarbon containing 1 to 8 heteroatoms selected from O and N, R2 is a methyl group, R3 is Ac(—(C═O)—CH3), R4 is hydrogen, and R a is hydrogen and R b is hydrogen.

[0466] In one embodiment of a compound of Formula (A), (I), or (I′), X is —O— and R 1 is —NH 2 , —NHR * , -N(R * )2, and R * is H or an aliphatic C1-C3 hydrocarbon, R2 is a methyl group, R3 is Ac(-(C=O)-CH3), R4 is hydrogen, and R a is hydrogen and R b is hydrogen.

[0467] In one embodiment of a compound of Formula (A), (I), or (I′), X is —NCH—, R is —OH, R is a methyl group, R is Ac(—(C═O)—CH), R is hydrogen, and R a is hydrogen and R b is hydrogen.

[0468] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (II):

[0469] [ka] During the ceremony, X is -O- and -NR * - selected from R a are hydrogen, -Cl, and -OR * is selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; *, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group; R N teeth,

[0470] [ka] is selected from, where the symbol

[0471] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OCor R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0472] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (II'):

[0473] [ka] During the ceremony, X is -O- and -NR * - selected from R a is hydrogen and -OR * is selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R *)-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group; R N teeth,

[0474] [ka] is selected from, where the symbol

[0475] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and FMOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0476] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (III):

[0477] [ka] During the ceremony, R a is hydrogen and -OR * is selected from R5 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R5 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R* )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof, provided that R5 is not an n-butyl group; R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and R N teeth,

[0478] [ka] is selected from, where the symbol

[0479] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OCor R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure.

[0480] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (III'):

[0481] [ka] During the ceremony, R a is hydrogen and -OR * is selected from R5 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R5 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof, provided that R5 is not an n-butyl group; R *are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; R N teeth,

[0482] [ka] is selected from, where the symbol

[0483] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure.

[0484] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (IV):

[0485] [ka] During the ceremony, R a is hydrogen and -OR * is selected from R5 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R5 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof; R N teeth,

[0486] [ka] is selected from, where the symbol

[0487] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0488] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (IV'), or a pharmaceutically acceptable salt thereof:

[0489] [ka] During the ceremony, R a is hydrogen and -OR * is selected from R5 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R5 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof; R N teeth,

[0490] [ka] is selected from, where the symbol

[0491] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0492] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (V):

[0493] [ka] During the ceremony, X is -O- and -NR * - selected from R a is hydrogen and -OR * is selected from R6 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R6 is selected from -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof, provided that R6 is not an n-butyl group; R N teeth,

[0494] [ka] is selected from, where the symbol

[0495] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0496] In one embodiment, a rifamycin analog compound of the present disclosure has the structure of formula (V'), or a pharmaceutically acceptable salt thereof:

[0497] [ka] During the ceremony, X is -O- and -NR * - selected from R a is hydrogen and -OR * is selected from R6 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R6 is selected from -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * and combinations thereof, provided that R6 is not an n-butyl group; R N teeth,

[0498] [ka] is selected from, where the symbol

[0499] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OCor R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0500] In another aspect, the disclosure provides a rifamycin analog compound having the structure of formula (B), or an intermediate or precursor thereof, or a pharmaceutically acceptable salt thereof:

[0501] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is hydrogen, R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R* )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0502] [ka] is selected from, where the symbol

[0503] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbon, and fluorenylmethyloxycarbonyl (F MOC ) and tert-butyloxycarbonyl (B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbons, and -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; Rb -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0504] In another aspect, the present disclosure provides a rifamycin analog compound having the structure of formula (B-1), or a pharmaceutically acceptable salt thereof:

[0505] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR* , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group; R N teeth,

[0506] [ka] is selected from, where the symbol

[0507] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OCor R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0508] In another aspect, the present disclosure provides a rifamycin analog compound having the structure of formula (B-2), or a pharmaceutically acceptable salt thereof:

[0509] [ka] During the ceremony, R N teeth,

[0510] [ka] is selected from, where the symbol

[0511] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure.

[0512] In another aspect, the present disclosure provides a rifamycin analog compound having the structure of formula (B-2), or a pharmaceutically acceptable salt thereof:

[0513] [ka] During the ceremony, R N teeth

[0514] [ka] where the symbol

[0515] [ka] represents a point of attachment, and R' and R" are selected from hydrogen and C1-C6 aliphatic hydrocarbons.

[0516] In one embodiment, the rifamycin analog compound has a structure according to the following formula:

[0517] [ka]

[0518] In any embodiment of the preceding formula, R is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-3 heteroatoms selected from O and N, wherein R is -F, -Cl, -Br, -I, -OH, C 1-3 Alkoxide, -NH2, -NHR * , -N(R * )2, -N(R * )3+ , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -N(R * )-(C=O)-R * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -O-(C=O)-H, -O-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, then R1 is not hydrogen.

[0519] In any embodiment of the preceding formula, R is an aliphatic C-C 20 Hydrocarbons and aromatics C1-C 20 Compounds are provided that are in combination with hydrocarbons.

[0520] In any embodiment of the preceding formula, R is an aliphatic C-C 20 Hydrocarbons and heteroaromatic C1-C 20 Compounds are provided that are in combination with hydrocarbons.

[0521] In embodiments of any of the above formulas, compounds are provided in which R 1 is selected from the following:

[0522] [ka]

[0523] In any embodiment of the preceding formula, R1 is -NH2, -NHR * , -N(R * )2, or -N(R * )-(C=O)-R * Aliphatic C1-C substituted with one or more of 20A compound is provided that is a hydrocarbon.

[0524] In embodiments of any of the preceding formulas, R1 is an aliphatic C1-C2 substituted with -NH-(C=O)-CH3 or -N(CH3)-(C=O)-CH3. 20 A compound is provided that is a hydrocarbon.

[0525] In any embodiment of the preceding formula, R a is hydrogen.

[0526] In any embodiment of the preceding formula, R a is -OH.

[0527] In any embodiment of the preceding formula, R a is -Cl.

[0528] In any embodiment of the preceding formula, R a -OR * and R * Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 A compound selected from the group consisting of: a cyclohexanediol, ...

[0529] In any embodiment of the preceding formula, R N is selected from the following:

[0530] [ka] In the formula, the symbol

[0531] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and BOC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure.

[0532] In any embodiment of the preceding formula, R N is selected from the following:

[0533] [ka] wherein R' is hydrogen, an aliphatic hydrocarbon, or a protecting group, and wherein the symbol

[0534] [ka] represents the point of attachment.

[0535] In any embodiment of the preceding formula, R * are independently, when each occurs, selected from hydrogen, aliphatic C1-C6 hydrocarbons, aromatic C6-C7 hydrocarbons, and combinations thereof, and further comprising 0-3 heteroatoms selected from O and N, and combinations thereof; * is an aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, and N, and combinations thereof.

[0536] Some exemplary, non-limiting embodiments of rifamycin analog compounds of the present disclosure are shown in Table 1 below.

[0537] [Table 1-1]

[0538] [Table 1-2]

[0539] [Table 1-3]

[0540] [Table 1-4]

[0541] [Table 1-5]

[0542] [Table 1-6]

[0543] [Table 1-7]

[0544] [Table 1-8]

[0545] [Table 1-9]

[0546] [Table 1-10]

[0547] In one embodiment, a rifamycin analog compound of the present disclosure has a structure selected from the group consisting of:

[0548] [ka]

[0549] In one aspect, the compounds of the present disclosure have the structure of formula (IA):

[0550] [ka] During the ceremony, X is -O-, -S-, and -NR * - selected from R1 is hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C5-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, aryl C6-C 20 Hydrocarbons, heteroaryl C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * Optionally substituted with one or more of: -CF, -O-CF, and combinations thereof; R2, R3, and R4 are independently straight-chain, branched-chain, or cyclic aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a are independently hydrogen, -F, -Cl, -Br, -I, -OH, -OR when present * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a and R b -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C5-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, aryl C6-C 20 Hydrocarbons, heteroaryl C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0551] In one embodiment, X is —O—, R1 is an aliphatic C1-C3 hydrocarbon, R2 is a methyl group, R3 is Ac(—(C═O)—CH3), R4 is hydrogen, and R a is hydrogen.

[0552] In one embodiment, X is —O—, R1 is a benzyl group, R2 is a methyl group, R3 is Ac(—(C═O)—CH3), R4 is hydrogen, and R a is hydrogen.

[0553] In one embodiment, X is —O—, R1 is an aliphatic C1-C8 hydrocarbon containing 1 to 8 heteroatoms selected from halogen, O, N, and S, R2 is a methyl group, R3 is Ac(—(C═O)—CH3), R4 is hydrogen, and R a is hydrogen.

[0554] In one embodiment, X is —O— and R 1 is —NH 2 , —NHR * , -N(R * )2, R2 is a methyl group, R3 is Ac(—(C═O)—CH3), R4 is hydrogen, and R a is hydrogen.

[0555] In one embodiment, X is —NCH—, R is —OH, R is a methyl group, R is Ac(—(C═O)—CH), R is hydrogen, and R a is hydrogen.

[0556] The present disclosure also includes salts of the compounds described herein. As used herein, "salt" refers to a derivative of a compound of the present disclosure, in which the parent compound is modified by converting an existing acid or base into its salt form. Examples of salts include, but are not limited to, mineral acids (e.g., HCl, HBr, HSO, etc.) or organic acids (e.g., acetic acid, benzoic acid, trifluoroacetate salts of basic residues such as amines, alkali (Li, Na, K, Mg, Ca) or organic salts (e.g., trialkylammonium) of acidic residues such as carboxylic acids). The salts of the present application can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of the compound with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a combination of the two. In some embodiments, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) may be used.

[0557] The present application also includes pharmaceutically acceptable salts of the compounds described herein. "Pharmaceutically acceptable salts" includes a subset of the above "salts," which are conventional non-toxic salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Berge, SM et al., Journal of Pharmaceutical Science, 1977, 66, 1, 1-19. The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical common sense, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0558] Preparation of compounds may require the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006. In one non-limiting embodiment, protecting groups may include 1-chloroethylcarbonyl (ACE), acetoyl, benzyl (Bn), benzyloxycarbonyl (CBz), formyl, methylcarbonyl, trifluoroacetyl, t-butoxycarbonyl (Boc), and fluorenylmethyloxycarbonyl (Fmoc).

[0559] The rifamycin analog compounds presented herein include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (conformational)) forms of the compounds, such as the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric mixtures of the compounds are within the scope of this disclosure. All tautomeric forms of the compounds presented herein are also within the scope of this disclosure.

[0560] The rifamycin analog compounds described herein also include all compounds that differ only in the presence of one or more isotopically enriched atoms, e.g., replacement of hydrogen by deuterium or tritium, 11 C. 13 C, or 14 Substitution of carbon by C-rich carbon, 17 Or 18 Replacement of oxygen with O-rich oxygen, or 15 Compounds having the present structures, except for the replacement of a nitrogen with an N-rich nitrogen, are within the scope of this disclosure.

[0561] Crystalline forms of the compounds of the present disclosure and their salts are also within the scope of the present disclosure. The compounds of the present disclosure may be isolated in various amorphous and crystalline polymorphic forms, including, but not limited to, anhydrous, hydrated, unsolvated, or solvated amorphous and crystalline polymorphic forms. Examples of hydrates include hemihydrates, monohydrates, dihydrates, etc. In some embodiments, the compounds of the present disclosure are anhydrous and unsolvated. "Anhydrous" means that the crystalline form of the compound does not substantially contain bound water in the crystal lattice structure, i.e., the compound does not form a crystalline hydrate.

[0562] Manufacturing method

[0563] In one aspect, the disclosure provides a method of making a rifamycin analog compound having the structure of formula (V), or a pharmaceutically acceptable salt thereof:

[0564] [ka] In the formula, X is —O— and —NR * - selected from R6 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof; R N teeth,

[0565] [ka] is selected from, where the symbol

[0566] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0 to 8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, said method comprising: (a) Rifamycin S, having the following structure:

[0567] [ka] with a compound having the structure of formula (VI):

[0568] [ka] In the formula, X' is -OH and -NHR * and (b) treating the product of step (a) with an oxidizing agent; Includes.

[0569] In one aspect, the disclosure provides a method of making a rifamycin analog compound having the structure of formula (V'), or a pharmaceutically acceptable salt thereof:

[0570] [ka] In the formula, X is —O— and —NR * - selected from R6 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof; R N teeth,

[0571] [ka] is selected from, where the symbol

[0572] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0 to 8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, said method comprising: (a) Rifamycin S, having the following structure:

[0573] [ka] with a compound having the structure of formula (VI'):

[0574] [ka] In the formula, X' is -OH and -NHR * and (b) treating the product of step (a) with an oxidizing agent; Includes.

[0575] In one aspect, the disclosure provides a method of making a compound having the structure:

[0576] [ka] The method comprises: (a) contacting Rifamycin S with a compound having the structure of formula (VII),

[0577] [ka] wherein PG is a protecting group; (b) treating the product of step (a) with an oxidizing agent; (c) removing the protecting group PG; Includes.

[0578] In one embodiment, the compound of formula (VII) is prepared by removing the protecting group PG′ from a compound of formula (VIII):

[0579] [ka] In the formula, the protecting groups PG and PG' may be the same or different.

[0580] In one embodiment, the compound of formula (VIII) is a compound of formula (IX)

[0581] [ka] with a compound of formula (X),

[0582] [ka] In the formula, the protecting groups PG and PG' may be the same or different.

[0583] In one aspect, the disclosure provides a method of making a compound having a structure of formula (XI), or a pharmaceutically acceptable salt thereof:

[0584] [ka] In the formula, R6 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; R6 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * Optionally substituted with one or more of: -CF, -O-CF, and combinations thereof; R N teeth,

[0585] [ka] is selected from, where the symbol

[0586] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and a combination thereof, which further comprises 0 to 8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, and the method comprises producing a compound having the structure of formula (XII):

[0587] [ka] with an alcohol having the structure R6-OH.

[0588] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XI'), or a pharmaceutically acceptable salt thereof:

[0589] [ka] In the formula, R6 is R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; R6 is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR *, -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * Optionally substituted with one or more of: -CF, -O-CF, and combinations thereof; R N teeth,

[0590] [ka] is selected from, where the symbol

[0591] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and a combination thereof, which further comprises 0 to 8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, and the method comprises producing a compound having the structure of formula (XII):

[0592] [ka] with an alcohol having the structure R6-OH.

[0593] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XIII), or a pharmaceutically acceptable salt thereof:

[0594] [ka] where A is a single bond (A is absent) or an aliphatic C1-C 20 selected from hydrocarbons, R cy is a C3-C alkyl group containing 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; 14 alicyclic hydrocarbons, where R cy is -F, -Cl, -Br, I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR *, -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; The method comprises:

[0595] [ka] and Structure R cy The method includes a step of contacting the compound with an alcohol having the formula -A-OH.

[0596] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XIII'), or a pharmaceutically acceptable salt thereof:

[0597] [ka] where A is a single bond (A is absent) or an aliphatic C1-C 20 selected from hydrocarbons, R cy is a C3-C alkyl group containing 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; 14 alicyclic hydrocarbons, where R cy is -F, -Cl, -Br, I, -OH, -OR *, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof; and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; The method comprises:

[0598] [ka] and Structure R cy The method includes a step of contacting the compound with an alcohol having the formula -A-OH.

[0599] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XIV), or a pharmaceutically acceptable salt thereof:

[0600] [ka] wherein Y, at each occurrence, is selected from -O- and -NR'R"-; n, at each occurrence, is an integer from 1 to 6; and R', R", and R'" are each independently selected from hydrogen, aliphatic C1-C 20 selected from hydrocarbons, The method comprises:

[0601] [ka] and structure R”R'NY-(CH2) n -Y-(CH2) n The method includes contacting the compound with an alcohol having an —OH group.

[0602] In one aspect, the disclosure provides a method of making a compound having the structure of formula (XIV'), or a pharmaceutically acceptable salt thereof:

[0603] [ka] wherein Y, at each occurrence, is selected from -O- and -NR'R"-; n, at each occurrence, is independently an integer from 1 to 6; and R', R", and R'" are each independently selected from hydrogen and aliphatic C1-C 20 selected from hydrocarbons, The method comprises:

[0604] [ka] and structure R”R'NY-(CH2) n -Y-(CH2) n The method includes contacting the compound with an alcohol having an —OH group.

[0605] In one embodiment, the compound of formula (XII) is prepared by contacting rifamycin S with 2-amino-5-bromophenol and treating the resulting product with an oxidizing agent.

[0606] In one embodiment, the compound of formula (XII') is prepared by contacting rifamycin S with 2-amino-4-bromophenol and treating the resulting product with an oxidizing agent.

[0607] Pharmaceutical Compositions and Dosage Forms

[0608] The present disclosure also provides pharmaceutical compositions comprising the compounds described herein. When used as pharmaceuticals, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition that is a combination of the compounds of the present disclosure with a pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical arts and can be administered by various routes. Such pharmaceutical compositions can be administered systemically. As used herein, the term "systemic" includes parenteral, topical, transdermal, oral, inhalation / pulmonary, rectal, nasal, buccal, and sublingual administration. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intracranial, and intraperitoneal administration. In some embodiments, the compounds are administered orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously in a therapeutically effective amount to treat a bacterial infection (e.g., a Staphylococcus aureus infection).

[0609] Pharmaceutical compositions containing the compounds of the present disclosure can be prepared in combination with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present disclosure, the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed in a carrier in the form of a container such as a capsule, sachet, or paper. When serving as a diluent, the excipient may be a solid, semi-solid, or liquid material that acts as a solvent, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft capsule, hard capsule, suppository, sterile injection solution, and sterile packaged powder containing, for example, up to 10% by weight of the active compound.

[0610] In some embodiments, the pharmaceutical compositions of the present disclosure are in liquid form. Non-limiting examples of liquid forms include emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids, etc. In some embodiments, the pharmaceutical compositions described herein are in liquid, semi-solid, or solid (e.g., powder) form. In specific embodiments, the pharmaceutical compositions described herein are in semi-solid form, such as gels, gel matrices, creams, pastes, etc. In some embodiments, the semi-solid form comprises a liquid solvent. In some embodiments, the pharmaceutical compositions of the present disclosure are in solid dosage forms such as tablets, granules, sachets, or powders. Also provided are pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the form of a dissolving tablet, dissolving wafer, capsule, or gel capsule. In certain embodiments, the solid dosage forms described herein comprise a solid solvent (e.g., those used in tablets) and / or a gaseous solvent (e.g., those used in DPIs).

[0611] In some embodiments, the compositions are in unit dosage formulations intended for oral, intranasal, intravenous, or other administration to a patient. The term "unit dosage form" refers to physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0612] The active compounds may be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount, however, it will be understood that the amount of compound actually administered will usually be determined by a physician depending on the relevant circumstances, including the disease being treated, the selected route of administration, the compound actually administered, the individual patient's age, weight, response, the severity of the patient's symptoms, etc.

[0613] In some embodiments, the compositions or unit dosage forms described herein are administered as an emulsion, solution, suspension, syrup, slurry, dispersion, colloid, dissolving tablet, dissolving wafer, capsule, gel capsule, semi-solid, solid gel, gel matrix, cream, paste, tablet, granule, sachet, powder, etc. In certain aspects, an individual is administered about 0.000001 mg to about 2000 mg, about 0.00001 mg to about 1000 mg, about 0.0001 mg to about 750 mg, about 0.001 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.1 mg to about 100 mg, about 0.5 mg to about 75 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, about 5 mg to about 20 mg, or about 7.5 mg to about 15 mg of a compound of formula (I) or a compound having a structure according to any embodiment of formula (A), (B), (I), (I'), (II), (II'), (III), (III'), (IV), (IV'), (V), or (V') as described herein per day or per administration.

[0614] In some embodiments, the compound of the present disclosure is present in a composition or unit dose described herein in an amount of about 0.01 mg to about 10 mg (e.g., about 0.1 to 10 mg, about 0.25 to 5 mg, about 0.25 to 2.5 mg, about 1 to 2 mg, about 2 to 3 mg, about 0.5 to about 2 mg, about 1 to about 2 mg, about 1 mg, or about 2 mg). In some embodiments, the amount of compound administered daily or in a unit dose is about 0.5 mg to about 3 mg, about 0.5 mg to about 4 mg, or about 0.35 mg to about 4 mg. In other embodiments, the amount of compound present in a unit dose or administered daily is about 1 to about 3 mg, about 1 to about 2 mg, or about 2 to about 3 mg.

[0615] In certain embodiments, about 0.05 mg to about 50 mg, about 0.25 mg to about 20 mg, about 0.25 mg to about 15 mg, about 0.25 mg to about 10 mg, or about 0.25 mg to about 5 mg (e.g., about 0.1 to about 5 mg, about 0.25 to about 2.5 mg, about 0.3 mg to about 2 mg, about 0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about 0.375 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg) of the compound is administered to a patient per day or per administration.

[0616] In some embodiments, the compound is present in a unit dose in an amount of about 5 mg to about 500 mg. In some embodiments, the amount of compound administered daily or in a unit dose is about 5 mg to about 300 mg. In other embodiments, the amount of compound present in a unit dose or administered daily is about 5 to about 250 mg, about 5 to about 200 mg, about 5 to about 150 mg, about 5 to about 100 mg, or about 5 to about 50 mg.

[0617] In preparing the formulation, the active compound can be milled to a suitable particle size before being combined with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, it can be milled to a substantially uniform distribution in the formulation, thereby adjusting the particle size, for example, to about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifiers, suspending agents, preservatives such as methyl- and propylhydroxy-benzoates, sweeteners, and flavoring agents. The compositions of the present disclosure can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by utilizing procedures well known in the art.

[0618] In preparing solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compound of Formula I. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, 0.000001 to 2000 mg of the active ingredient of the present application.

[0619] Tablets or pills containing a compound of Formula I can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of a membrane over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0620] Liquid forms in which the compounds and compositions of the present application can be incorporated for oral administration or injection include aqueous solutions, suitably flavored syrups, aqueous suspensions, oily suspensions, and flavored emulsions including edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and other similar pharmaceutical vehicles.

[0621] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered orally or via the nasal respiratory route for local or systemic effect. Compositions can be nebulized using an inert gas. Nebulized solutions can be inhaled directly from a nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate form.

[0622] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions may be packaged for ready use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3 to 11, more preferably 5 to 9. It is understood that pharmaceutical salts may be formed using some of the excipients, carriers, or stabilizers described above.

[0623] Therapeutic dosages of compounds of the present disclosure may vary depending, for example, on the particular use for which the treatment is made, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. The dosage will likely depend on variables such as the type of disease or disorder and its progression, the general health of the particular patient, the overall biological effect of the compound selected, and the route of administration. Effective dosages may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0624] The present application further provides pharmaceutical kits useful, for example, for treating infectious diseases (e.g., Staphylococcus aureus infections), which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits may further include, if desired, one or more of a variety of conventional pharmaceutical kit components, such as one or more pharmaceutically acceptable carriers, additional containers, etc., as will, of course, be readily apparent to those skilled in the art. Instructions indicating the amounts of components to be administered, administration guidelines, and / or component mixing guidelines can also be included in the kit, either as an insert or label.

[0625] The delivery device is important not only for delivering the compounds of the present disclosure, but also for providing a suitable storage environment. This includes protection from microbial contamination and chemical degradation. The device and formulation must be suitable to avoid possible leaching or adsorption. The delivery device (or its packaging) can optionally be provided with a label and / or instructions indicating that the composition should be used intranasally.

[0626] How to use

[0627] In another aspect, the disclosure provides a method of preventing or inhibiting bacterial growth, the method comprising administering an effective amount of a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof:

[0628] [ka] During the ceremony, X is -O-, -S-, and -NR * - selected from Za and Zb are independently hydrogen, -Cl, -Br, -OR1, and -R N wherein at least one of Za or Zb is not hydrogen; and wherein R1 is hydrogen, R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0629] [ka] is selected from, where the symbol

[0630] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and alkyl groups such as F MOC and B OC or R′ and R″ together form an aliphatic cyclic structure, such as an aliphatic monocyclic structure, an aliphatic bicyclic structure, or an aliphatic polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbons, and -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; Rb -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0631] In another aspect, the disclosure provides a method for preventing or inhibiting bacterial growth, the method comprising administering an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0632] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R* )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0633] [ka] is selected from, where the symbol

[0634] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0635] In another aspect, the disclosure provides a method of preventing or inhibiting bacterial growth, the method comprising administering an effective amount of a compound having the structure of formula (I'), or a pharmaceutically acceptable salt thereof:

[0636] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R *)2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0637] [ka] is selected from, where the symbol

[0638] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0639] In another aspect, the disclosure provides a method of preventing or inhibiting bacterial growth, the method comprising administering an effective amount of a compound having the structure of Formula (B), or a pharmaceutically acceptable salt thereof:

[0640] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is hydrogen, R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR *, -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0641] [ka] is selected from, where the symbol

[0642] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbon, and fluorenylmethyloxycarbonyl (F MOC ) and tert-butyloxycarbonyl (B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbons, and -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR *, -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0643] In another aspect, the disclosure provides a method of preventing or inhibiting bacterial growth, the method comprising administering an effective amount of a rifamycin analog compound having a structure according to any one of formulas (IA), (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (B-1), and (B-2) provided herein. In one embodiment, the bacteria is a gram-positive bacteria.

[0644] In one embodiment, the bacterium is penicillin-resistant.

[0645] In one embodiment, the bacterium is Staphylococcus aureus.

[0646] In one embodiment, the bacterium is a resistant Staphylococcus aureus strain selected from MRSA and VRSA.

[0647] In one embodiment, the bacterium is methicillin-resistant Staphylococcus aureus (MRSA).

[0648] In one embodiment, the bacterium is vancomycin-resistant Staphylococcus aureus (VRSA).

[0649] In one embodiment, the bacterium is methicillin-sensitive Staphylococcus aureus (MSSA).

[0650] In yet another aspect, the disclosure provides a method of treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (A), or a pharmaceutically acceptable salt thereof;

[0651] [ka] During the ceremony, X is -O-, -S-, and -NR * - selected from Za and Zb are independently hydrogen, -Cl, -Br, -OR1, and -R N wherein at least one of Za or Zb is not hydrogen; and wherein R1 is hydrogen, R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; *, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0652] [ka] is selected from, where the symbol

[0653] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbons, and -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0654] In another aspect, the disclosure provides a method of treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof;

[0655] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R *, -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0656] [ka] is selected from, where the symbol

[0657] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR *, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0658] In another aspect, the disclosure provides a method of treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (I'), or a pharmaceutically acceptable salt thereof;

[0659] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R *)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0660] [ka] is selected from, where the symbol

[0661] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbons, and F MOC and B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR* optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0662] In yet another aspect, the disclosure provides a method of treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (B):

[0663] [ka] During the ceremony, X is -O- and -NR * - selected from R1 is hydrogen, R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R N teeth,

[0664] [ka] is selected from, where the symbol

[0665] [ka] represents a point of attachment, and R', R", and R''' are hydrogen, C1-C6 aliphatic hydrocarbon, and fluorenylmethyloxycarbonyl (F MOC ) and tert-butyloxycarbonyl (B OC or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; R2, R3, and R4 are independently hydrogen, aliphatic C1-C 20 Hydrocarbons, and -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b is hydrogen, -F, -Cl, -Br, -I, -OH, -OR * , -(C=O)-R * , -CHO, -CO2H, -CO2R * , and aliphatic C1-C20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O, and S; R b -F, -Cl, -Br, -I, -OH, -OR * and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0666] In another aspect, the disclosure provides a method of treating a bacterial infection in a subject, the method comprising administering an effective amount of a rifamycin analog compound having a structure according to any one of formulas (IA), (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (B-1), and (B-2) provided herein. In one embodiment, the bacterial infection is a gram-positive bacterial infection.

[0667] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[0668] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[0669] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[0670] In one embodiment, the subject is a human.

[0671] In one embodiment, the method further comprises administering a second therapeutic agent.

[0672] In one embodiment, the second therapeutic agent is a second antibiotic.

[0673] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[0674] In one embodiment, the second antibiotic is selected from an aminoglycoside, a beta-lactam, a macrolide, a cyclic peptide, a tetracycline, a fluoroquinoline, a fluoroquinolone, and an oxazolidinone.

[0675] In one embodiment, the second antibiotic is selected from clindamycin, novobiocin, retapamulin, daptomycin, sitafloxacin, teicoplanin, triclosan, naphthyridone, radezolid, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin.

[0676] In one embodiment, the compound is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[0677] In another aspect, the disclosure provides a method for preventing or inhibiting bacterial growth, the method comprising administering an effective amount of a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0678] [ka] During the ceremony, X is -O-, -S-, and -NR * - selected from R1 is hydrogen, aliphatic C1-C 20Hydrocarbons, aromatic C5-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR; * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R * )3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R2, R3, and R4 are independently straight-chain, branched-chain, or cyclic aliphatic C1-C20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b are each, when present, a hydrogen atom, and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0679] In yet another aspect, the disclosure provides a method of treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (I'), or a pharmaceutically acceptable salt thereof;

[0680] [ka] During the ceremony, X is -O-, -S-, and -NR * - selected from R1 is hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R is selected from -F, -Cl, -Br, -I, -OH, -OR * , -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -N(R * )-OH, -ON(R * )2, -N(R * )-OR * , -CN, -NC, -(C=O)-R * , -CHO, -CO2H, -CO2R * , -(C=O)-SR * , -O-(C=O)-H, -O-(C=O)-R * , -S-(C=O)-R * , -(C=O)-NH2, -(C=O)-N(R * )2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R * )2, -N(R * )-CHO, -N(R * )-(C=O)-R * , -SCN, -NCS, -NSO, -SSR * , -SO2R * , -SO2-N(R * )2, -S(=O)-OR * , -S(=O)-R * , -Si(R *)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, X is -O-, and R a is hydrogen, R1 is not hydrogen, R2, R3, and R4 are independently straight-chain, branched-chain, or cyclic aliphatic C1-C 20 Hydrocarbon, or -(C=O)-R * each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S; R a is hydrogen, F, -Cl, -Br, -I, -OH, -OR * , -NH2, -NHR * , -N(R * )2, -N(R * )3 + , -(C=O)-R * , -CHO, -CO2H, -CO2R * , -SR * , -SO2R * , and aliphatic C1-C 20 hydrocarbons, which further contain 0-8 heteroatoms selected from halogen, O, N, and S; R a -F, -Cl, -Br, -I, -OH, -OR * optionally substituted with one or more of R b are each, when present, a hydrogen atom, and R * are independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0681] In one aspect, the present disclosure provides a method for preventing or inhibiting bacterial growth, the method comprising administering an effective amount of a rifamycin analog compound of the present disclosure, a pharmaceutical composition comprising a rifamycin analog compound of the present disclosure, or a pharmaceutical dosage form comprising a rifamycin analog compound of the present disclosure.

[0682] In another aspect, the present disclosure provides a method for treating a bacterial infection in a subject, the method comprising administering to the subject an effective amount of a rifamycin analog compound of the present disclosure, a pharmaceutical composition comprising a rifamycin analog compound of the present disclosure, or a pharmaceutical dosage form comprising a rifamycin analog compound of the present disclosure.

[0683] In one embodiment, the compound, composition, or dosage form is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[0684] Anti-MSR1 antibodies suitable for ADC

[0685] The antibody drug conjugates described herein may comprise a full-length anti-MSR1 antibody (e.g., an IgG1 or IgG4 antibody) or may comprise only the antigen-binding portion (e.g., a Fab, F(ab')2, or scFv fragment), and may be modified to affect function, for example, to eliminate residual effector function (Reddy et al., 2000, J. Immunol. 164:1925-1933).

[0686] Embodiments of the antibody drug conjugates described herein may include the anti-MSR1 antibodies listed in Tables 9 and 10. Table 9 lists the amino acid sequence identifiers for the heavy chain variable region (HCVR), light chain variable region (LCVR), heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), and light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of exemplary anti-MSR1 antibodies. Table 10 lists the nucleic acid sequence identifiers for the HCVR, LCVR, HCDR1, HCDR2 HCDR3, LCDR1, LCDR2, and LCDR3 of exemplary anti-MSR1 antibodies.

[0687] Antibodies or antigen-binding fragments suitable for the antibody drug conjugates described herein include those that specifically bind to MSR1 and contain an HCVR that includes an amino acid sequence selected from any of the HCVR amino acid sequences listed in Table 9, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0688] Furthermore, a suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises an LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences listed in Table 9, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0689] Additionally, suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise an HCVR and LCVR amino acid sequence pair (HCVR / LCVR) comprising any of the HCVR amino acid sequences listed in Table 9 paired with any of the LCVR amino acid sequences listed in Table 9. Certain embodiments relate to antibody-drug conjugates, or antigen-binding fragments thereof, comprising an antibody or antigen-binding fragment comprising an HCVR / LCVR amino acid sequence pair contained within any of the exemplary anti-MSR1 antibodies listed in Table 9. In some embodiments, the HCVR / LCVR amino acid sequence pair is selected from the group consisting of 2 / 10, 23 / 42, 50 / 58; 90 / 98, and 282 / 290.

[0690] Antibodies or antigen-binding fragments thereof suitable for the antibody drug conjugates described herein include those that specifically bind to MSR1 and comprise a heavy chain CDR1 (HCDR1) that comprises an amino acid sequence selected from any of the HCDR1 amino acid sequences listed in Table 9, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0691] Furthermore, suitable antibodies or antigen-binding fragments thereof that specifically bind MSR1 comprise a heavy chain CDR2 (HCDR2) comprising an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in Table 9, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0692] Furthermore, a suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises a heavy chain CDR3 (HCDR3) comprising an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in Table 9, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0693] Antibodies or antigen-binding fragments thereof suitable for the antibody drug conjugates described herein include those that specifically bind to MSR1 and comprise a light chain CDR1 (LCDR1) comprising an amino acid sequence selected from any of the LCDR1 amino acid sequences listed in Table 9, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0694] Furthermore, a suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises a light chain CDR2 (LCDR2) comprising an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in Table 9, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0695] Furthermore, a suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises a light chain CDR3 (LCDR3) comprising an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in Table 9, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0696] Furthermore, suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise an HCDR3 and LCDR3 amino acid sequence pair (HCDR3 / LCDR3) comprising any of the HCDR3 amino acid sequences listed in Table 9 paired with any of the LCDR3 amino acid sequences listed in Table 9. Certain embodiments relate to antibodies or antigen-binding fragments thereof comprising an HCDR3 / LCDR3 amino acid sequence pair contained within any of the exemplary anti-MSR1 antibodies listed in Table 9. In some embodiments, the HCDR3 / LCDR3 amino acid sequence pair is selected from the group consisting of 8 / 16, 40 / 48, 56 / 64; 96 / 104, and 288 / 296.

[0697] Antibodies or antigen-binding fragments thereof suitable for the antibody drug conjugates described herein include those that specifically bind to MSR1 and comprise the six CDR sets (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any of the exemplary anti-MSR1 antibodies listed in Table 9. In certain embodiments, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set is selected from the group consisting of: 4-6-8-12-14-16; 36-38-40-44-46-48; 52-54-56-60-62-64; 92-94-96-100-102-104, and 284-286-288-292-294-296.

[0698] In related embodiments, a suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within the HCVR / LCVR amino acid sequence pair defined by any of the exemplary anti-MSR1 antibodies listed in Table 9. For example, the present disclosure includes a suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 and comprises a set of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences contained within the HCVR / LCVR amino acid sequence selected from the group consisting of 2 / 10, 23 / 42, 50 / 58, 90 / 98, and 282 / 290. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, for example, Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273: 927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86: 9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0699] Also provided herein are nucleic acid molecules encoding anti-MSR1 antibodies or portions thereof for preparing the antibody-drug conjugates described herein. For example, provided herein are nucleic acid molecules encoding any of the HCVR amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the HCVR nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0700] Also provided herein are nucleic acid molecules encoding any of the LCVR amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the LCVR nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0701] Also provided herein are nucleic acid molecules encoding any of the HCDR1 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the HCDR1 nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0702] Also provided herein are nucleic acid molecules encoding any of the HCDR2 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the HCDR2 nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0703] Also provided herein are nucleic acid molecules encoding any of the HCDR3 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the HCDR3 nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0704] Also provided herein are nucleic acid molecules encoding any of the LCDR1 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the LCDR1 nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0705] Provided herein are nucleic acid molecules encoding any of the LCDR2 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the LCDR2 nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0706] Provided herein are nucleic acid molecules encoding any of the LCDR3 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the LCDR3 nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[0707] Also provided herein are nucleic acid molecules encoding HCVRs, wherein the HCVRs may comprise a set of three CDRs (i.e., HCDR1-HCDR2-HCDR3), wherein the HCDR1-HCDR2-HCDR3 amino acid sequence set is as defined by any of the exemplary anti-MSR1 antibodies listed in Table 9.

[0708] Also provided herein are nucleic acid molecules encoding LCVRs, wherein the LCVRs may comprise a set of three CDRs (i.e., LCDR1-LCDR2-LCDR3), wherein the set of LCDR1-LCDR2-LCDR3 amino acid sequences is as defined by any of the exemplary anti-MSR1 antibodies listed in Table 9.

[0709] Also provided herein are nucleic acid molecules encoding both an HCVR and an LCVR, wherein the HCVR may comprise the amino acid sequence of any of the HCVR amino acid sequences listed in Table 9, and wherein the LCVR may comprise the amino acid sequence of any of the LCVR amino acid sequences listed in Table 9. In certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any of the HCVR nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto, and a polynucleotide sequence selected from any of the LCVR nucleic acid sequences listed in Table 10, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity thereto. In certain embodiments according to this aspect of the disclosure, the nucleic acid molecule encodes an HCVR and an LCVR, wherein both the HCVR and LCVR are derived from the same anti-MSR1 antibody listed in Table 9.

[0710] Also provided herein are recombinant expression vectors capable of expressing polypeptides comprising the heavy or light chain variable regions of anti-MSR1 antibodies for preparing the antibody-drug conjugates described herein. For example, embodiments include recombinant expression vectors comprising any of the above-mentioned nucleic acid molecules, i.e., nucleic acid molecules encoding any of the HCVR, LCVR, and / or CDR sequences listed in Table 9. Also included within the scope of the present disclosure are host cells into which such vectors have been introduced, as well as methods for producing antibodies or portions thereof for preparing the antibody-drug conjugates described herein by culturing the host cells under conditions that allow the production of antibodies or antibody fragments and recovering the antibodies and antibody fragments so produced.

[0711] Anti-MSR1 antibodies suitable for use in the antibody-drug conjugates described herein include those with modified glycosylation patterns. In some embodiments, modifications to remove undesired glycosylation sites or antibodies lacking fucose moieties present in the oligosaccharide chains may be useful, for example, to improve antibody-dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, galactosylation modifications can be performed to modify complement-dependent cytotoxicity (CDC).

[0712] According to certain embodiments, the antibody drug conjugates of the present disclosure comprise an anti-MSR1 antibody comprising an Fc domain containing one or more mutations that enhance or decrease antibody binding to the FcRn receptor, e.g., at acidic pH compared to neutral pH. For example, the C of the Fc domain H 2 or C HProvided herein are antibody-drug conjugates comprising anti-MSR1 antibodies containing mutations in three regions, where the mutations increase the affinity of the Fc domain for FcRn in acidic environments (e.g., endosomes, where the pH ranges from about 5.5 to about 6.0). Such mutations may increase the serum half-life of the antibody when administered to an animal. Non-limiting examples of such Fc modifications include, for example, modifications at positions 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L / Y / F / W, or T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D, or T); or modifications at positions 428 and / or 433 (e.g., H / L / R / S / P / Q, or K) and / or 434 (e.g., H / F or Y); or modifications at positions 250 and / or 428; or modifications at positions 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, modifications may include 428L (e.g., M428L) and 434S (e.g., N434S) modifications; 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modifications; 433K (e.g., H433K) and 434 (e.g., 434Y) modifications; 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modifications; 250Q and 428L modifications (e.g., T250Q and M428L); and 307 and / or 308 modifications (e.g., 308F or 308P).

[0713] For example, embodiments include antibody-drug conjugates comprising an anti-MSR1 antibody comprising an Fc domain, wherein the Fc domain comprises one or more pairs or groups selected from the group consisting of 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T, and 256E (e.g., M252Y, S254T, and T256E); 428L and 434S (e.g., M428L and N434S); and 433K and 434F (e.g., H433K and N434F). All possible combinations of the foregoing Fc domain mutations, as well as other mutations in the antibody variable domains disclosed herein, are contemplated as being within the scope of the present disclosure.

[0714] Biological properties of anti-MSR1 antibodies

[0715]

[0010] Embodiments include antibody-drug conjugates, including rifamycin analogs and antibodies and antigen-binding fragments thereof, that bind to human MSR1 with high affinity. For example, the present disclosure provides antibody-drug conjugates that bind to the extracellular domain of human MSR1 expressed with an N-terminal nonahistidine tag (SEQ ID NO: 688) (e.g., His9-hMSR1) with a K of less than about 10 nM as measured by surface plasmon resonance at 25°C or 37°C, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. DThe present invention also includes an antibody-drug conjugate comprising an anti-MSR1 antibody that binds at According to certain embodiments, an antibody drug conjugate comprising an anti-MSR1 antibody has a K of less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, less than about 10 pM, as measured by surface plasmon resonance, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. D and binds to human MSR1 at 37° C. In some embodiments, the K is less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, or less than about 20 pM as measured by surface plasmon resonance, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. D and an antibody-drug conjugate comprising an anti-MSR1 antibody disclosed herein that binds to human MSR1 at 25°C.

[0716] Embodiments include antibody drug conjugates comprising antibodies and antigen-binding fragments thereof that bind to monkey MSR1 with high affinity, e.g., a K of less than about 20 nM as measured by surface plasmon resonance at 25°C or 37°C, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. DDisclosed herein is an antibody drug conjugate comprising an anti-MSR1 antibody that binds to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag ("hexahistidine" disclosed as SEQ ID NO: 689) (e.g., HMM-mfMSR1). According to certain embodiments, the antibody drug conjugate has a cytotoxicity of less than about 20 nM, less than about 18 pM, less than about 15 nM, less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, or less than about 3 nM, as measured by surface plasmon resonance, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. , less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, or less than about 10 pM D An antibody-drug conjugate comprising an anti-MSR1 antibody that binds to monkey MSR1 at 37°C is provided. In some embodiments, an antibody drug conjugate comprising an anti-MSR1 antibody disclosed herein has a K of less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, or less than about 20 pM as measured by surface plasmon resonance, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. D and binds to monkey MSR1 at 25°C.

[0717] The present disclosure also provides compounds having a dissociation half-life (t) of greater than about 5 minutes, as measured by surface plasmon resonance at 25° C. or 37° C., using, for example, the assay format defined in Example 25 herein or a substantially similar assay. 1 / 2), and antibody-drug conjugates comprising antibodies and antigen-binding fragments thereof that bind to the extracellular domain of human MSR1 expressed with an N-terminal nonahistidine tag (SEQ ID NO: 688) (e.g., His9-hMSR1). According to certain embodiments, the t is greater than about 4 minutes, greater than about 5 minutes, greater than about 6 minutes, greater than about 8 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 14 minutes, greater than about 16 minutes, greater than about 18 minutes, greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 70 minutes, greater than about 80 minutes, greater than about 90 minutes, greater than about 120 minutes, greater than about 150 minutes, greater than about 180 minutes, greater than about 210 minutes, greater than about 240 minutes, or greater, as measured by surface plasmon resonance, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. 1 An antibody-drug conjugate comprising an anti-MSR1 antibody that binds to human MSR1 at 37°C at 1 / 2 is provided.

[0718] Embodiments also include antibody-drug conjugates comprising antibodies and antigen-binding fragments thereof capable of binding with high affinity to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag ("hexahistidine" disclosed as SEQ ID NO: 689) (e.g., HMM-mfMSR1). For example, the present disclosure includes antibody-drug conjugates having a K of less than about 20 nM, as measured by surface plasmon resonance at 25° C. or 37° C., e.g., using the assay format defined in Example 25 herein or a substantially similar assay. Dand an antibody-drug conjugate comprising an anti-MSR1 antibody that binds to HMM-mfMSR1 at the According to certain embodiments, the K is less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 150 pM, less than about 100 pM, less than about 90 pM, about 80 pM, less than about 70 pM, less than about 60 pM, or less than about 50 pM, as measured by surface plasmon resonance, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. D and an antibody-drug conjugate comprising an anti-MSR1 antibody that binds to HMM-mfMSR1 at 37°C. In some embodiments, the anti-MSR1 antibodies disclosed herein have a K of less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 150 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, or less than about 50 pM, as measured by surface plasmon resonance, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. D and binds to HMM-mfMSR1 at 25°C.

[0719] Embodiments include those having a dissociation half-life (t) of greater than about 55 minutes, as measured by surface plasmon resonance at 25° C. or 37° C., e.g., using the assay format defined in Example 25 herein or a substantially similar assay. 1Also included are antibody-drug conjugates comprising antibodies and antigen-binding fragments thereof that bind to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag ("hexahistidine" disclosed as SEQ ID NO: 689) at the N-terminal myc-myc-hexahistidine tag (SEQ ID NO: 689) (e.g., HMM-mfMSR1). According to certain embodiments, the t is greater than about 1 minute, greater than about 2 minutes, greater than about 3 minutes, greater than about 4 minutes, greater than about 5 minutes, greater than about 6 minutes, greater than about 8 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 14 minutes, greater than about 16 minutes, greater than about 18 minutes, greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 70 minutes, greater than about 80 minutes, greater than about 90 minutes, greater than about 120 minutes, greater than about 150 minutes, greater than about 180 minutes, greater than about 210 minutes, or more, as measured by surface plasmon resonance, e.g., using the assay format defined in Example 25 herein or a substantially similar assay. 1 An antibody-drug conjugate comprising an anti-MSR1 antibody that binds to dimeric human MSR1 at 37°C at 1 / 2 is provided.

[0720] Embodiments also include antibody drug conjugates, including antibodies and antigen-binding fragments thereof, that bind to an engineered cell surface expressed by hMSR1 at a binding ratio of at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 12-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, or more, of cells expressing the engineered hMSR1 compared to cells not expressing the engineered hMSR1, as measured by an antibody binding assay, e.g., using the assay format defined in Example 27 herein or a substantially similar assay. In some embodiments, provided herein are antibody drug conjugates comprising an antibody that binds to cells having endogenously expressed hMSR1 at a binding ratio of at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold or more, at least about 12-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold or more to cells expressing endogenous hMSR1 versus cells not expressing endogenous hMSR1, as measured by an antibody binding assay, e.g., using the assay format defined in Example 27 herein or a substantially similar assay.In some embodiments, the antibody drug conjugate comprises an MSR1 antibody or antigen-binding fragment disclosed herein that binds to the surface of engineered cells expressing mouse MSR1 at a binding ratio of at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 12-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, or more, of cells expressing the engineered mouse MSR1 compared to cells not expressing the engineered mouse MSR1, as measured by an antibody binding assay, e.g., using the assay format defined in Example 27 herein or a substantially similar assay.

[0721] The antibody-drug conjugate comprises the antibody disclosed herein, which may possess one or more of the aforementioned biological properties, or any combination thereof. The foregoing list of biological properties of the antibodies disclosed herein is not intended to be exhaustive. Other biological properties of the antibodies disclosed herein will be apparent to those skilled in the art upon reviewing this disclosure, including the Examples herein.

[0722] Anti-WTA antibodies suitable for ADC According to some embodiments, the antibody-drug conjugate of the present disclosure may comprise an anti-WTA antibody or its antigen-binding fragment. Such an anti-WTA antibody or its antigen-binding fragment binds to wall teichoic acid (WTA), which is expressed on many Gram-positive bacteria, including Staphylococcus aureus. Anti-WTA antibodies can be selected and produced by the methods taught in, for example, U.S. Patent No. 8,283,294; Meijer PJ et al. (2006) J Mol Biol. 358(3):764-72; Lantto J, et al. (2011) J Virol. 85(4):1820-33; and WO2016090038, each of which is incorporated herein by reference in its entirety for all purposes.

[0723] The chemical structure of WTA varies among organisms. In S. aureus, WTA is covalently linked to the 6-OH of N-acetylmuramic acid (MurNAc) via a disaccharide composed of N-acetylglycosamine (GlcNAc)-l-P and N-acetylmannoseamine (ManNAc), which is then covalently linked to approximately two or three units of glycerol phosphate. The actual WTA polymer then consists of approximately 11–40 repeating units of ribitol phosphate (RboP). The stepwise synthesis of WTA is first initiated by an enzyme called TagO; S. aureus strains lacking the TagO gene (due to gene deletion) do not produce WTA. The repeating units can be further modified with D-alanine (D-Ala) at the C2-OH and / or N-acetylglucosamine (GlcNAc) at the C4-OH position via α- or β-glycosidic bonds. Depending on the S. aureus strain or bacterial growth phase, the glycosidic bond can be α-, β-, or a mixture of the two anomers. These GlcNAc sugar modifications are mediated by two specific S. aureus glycosyltransferases (Gtfs): TarM Gtf mediates α-glycosidic bonds, while TarS Gtf mediates β-glycosidic bonds.

[0724] The anti-WTA antibody suitable for the ADC of the present disclosure can be an anti-WTAα or anti-WTAβ antibody.The anti-WTA antibody can be cloned from the B cells of a person infected with Staphylococcus aureus.In one embodiment, the anti-WTA antibody is a human monoclonal antibody.The ADC of the present disclosure includes chimeric antibodies and humanized antibodies comprising the CDRs of the anti-WTA antibodies described herein.

[0725] The antibody drug conjugates of the present disclosure can include any one of the anti-WTA antibodies, or antigen-binding fragments thereof, described herein. In some embodiments, the anti-WTA antibody, or antigen-binding fragment thereof, binds to Staphylococcus aureus.

[0726] In some embodiments, the antibody-drug conjugate of the present disclosure comprises an anti-WTAα monoclonal antibody, or an antigen-binding fragment thereof. As a non-limiting example, the anti-WTAα antibody, or an antigen-binding fragment thereof, comprises: (a) a complementarity-determining region (CDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence set forth in Table 2A; and (b) a CDR of the light chain variable region (LCVR) comprising the amino acid sequence set forth in Table 2A.

[0727] [Table 2A]

[0728] In one embodiment, the anti-WTAα antibody, or antigen-binding fragment thereof, comprises: (i) an HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 470, 476, 482, and 488; (ii) an HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 471, 477, 483, and 489; (iii) an HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 472, 478, 484, a...

Claims

1. Formula (V) 【Chemical 1】 (In the formula, X is —O— and —NR ＊ - is selected from, R ａ is hydrogen and -OR ＊ is selected from R ６ is R Ｎ , aliphatic C １ -C ２０ Hydrocarbons, aromatic C ５ -C ２０ Hydrocarbons, heteroaromatic C １ -C ２０ Hydrocarbons, cycloaliphatic C ３ -C ２０ Hydrocarbons, heterocyclic C １ -C ２０ hydrocarbons, and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S; R ６ is -OH, -OR ＊ , -NH ２ , -NHR ＊ , -N(R ＊ ) ２ , -N(R ＊ ) ３ ＋ , -N(R ＊ )-(C=O)-R ＊ , -(C=O)-R ＊ , —CHO, —CO ２ H, -CO ２ R ＊ and combinations thereof, where R ６ is not an n-butyl group, R Ｎ teeth, 【Chemistry 2】 is selected from, where the symbol 【Chemistry 3】 represents a point of attachment, and R', R", and R''' are hydrogen, C １ -C ６ Aliphatic hydrocarbons, and F ＭＯＣ and B ＯＣ or R′ and R″ together form an aliphatic monocyclic, bicyclic, or polycyclic structure; and R ＊ are independently selected from hydrogen, aliphatic C １ -C ２０ Hydrocarbons, aromatic C ５ -C ２０ Hydrocarbons, heteroaromatic C １ -C ２０ Hydrocarbons, cycloaliphatic C ３ -C ２０ Hydrocarbons, heterocyclic C １ -C ２０ hydrocarbons, and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof. or a pharmaceutically acceptable salt thereof.

2. R Ｎ but, 【Chemistry 4】 and R', R", and R'" are independently, when present, selected from hydrogen and an aliphatic hydrocarbon, wherein 【Chemistry 5】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein represents a point of attachment.

3. R ＊ are independently hydrogen, aliphatic C １ -C ６ Hydrocarbons, aromatic C ６ -C ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl, alkyl aryl, alkyl methacrylate, alkoxy, alkoxysilyl ...

4. below, 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 1. A compound having a structure selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

5. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. 10. A pharmaceutical dosage form comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. 10. Use of a compound according to claim 1 in the preparation of a medicament for preventing or inhibiting bacterial growth.

8. The use according to claim 7, wherein the bacterium is a gram-positive bacterium.

9. The use according to claim 7, wherein the bacterium is Staphylococcus aureus.

10. 8. The use of claim 7, wherein the bacteria is selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and methicillin-sensitive Staphylococcus aureus (MSSA).

11. 10. Use of a compound according to claim 1 in the preparation of a medicament for the treatment of a bacterial infection.

12. The use according to claim 11, wherein the bacterial infection is a gram-positive bacterial infection.

13. The use according to claim 11, wherein the bacterial infection is a Staphylococcus aureus infection.

14. 12. The use of claim 11, wherein the bacterial infection is selected from the group consisting of a methicillin-resistant Staphylococcus aureus (MRSA) infection, a vancomycin-resistant Staphylococcus aureus (VRSA) infection, and a methicillin-sensitive Staphylococcus aureus (MSSA) infection.

15. 12. The use according to claim 11, wherein the treatment is carried out in a subject, and the subject is a human.

16. 12. The use of claim 11, wherein the treatment further comprises administering a second therapeutic agent, wherein the second therapeutic agent is an antibiotic selected from an aminoglycoside, a beta-lactam, a macrolide, a cyclic peptide, a tetracycline, a fluoroquinoline, a fluoroquinolone, and an oxazolidinone.

17. 10. An antibody drug conjugate comprising an antibody or antigen-binding fragment thereof conjugated to the compound of claim 1 via a linker or linker-spacer.

18. 18. The antibody-drug conjugate of claim 17, wherein the antibody or antigen-binding fragment thereof binds to an infection-associated target selected from the group consisting of macrophage scavenger receptor 1 (MSR1), wall teichoic acid (WTA), and Staphylococcus aureus protein A.

19. 18. The antibody drug conjugate of claim 17, wherein the antibody or antigen-binding fragment thereof comprises a C103S mutation in the light chain.

20. 18. The antibody drug conjugate of claim 17, wherein the antibody or antigen-binding fragment thereof is conjugated to the compound of claim 1 at position 103 of the light chain.

21. The linker or linker spacer is 【Chemistry 11】 18. The antibody drug conjugate of claim 17, selected from:

22. The antibody-drug conjugate of claim 17, having a drug-antibody ratio (DAR) of between 1 and 8.

23. 20. Use of the antibody drug conjugate of claim 17 in the preparation of a medicament for preventing or inhibiting bacterial growth.

24. 24. The use according to claim 23, wherein the bacterium is a gram-positive bacterium.

25. 24. The use of claim 23, wherein the bacteria is selected from methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and methicillin-sensitive Staphylococcus aureus (MSSA).

26. 20. Use of the antibody drug conjugate of claim 17 in the preparation of a medicament for the treatment of a bacterial infection.

27. 27. The use according to claim 26, wherein the bacterial infection is a gram-positive bacterial infection.

28. 27. The use of claim 26, wherein the bacterial infection is selected from a methicillin-resistant Staphylococcus aureus (MRSA) infection, a vancomycin-resistant Staphylococcus aureus (VRSA) infection, and a methicillin-sensitive Staphylococcus aureus (MSSA) infection.

29. 27. The use of claim 26, wherein the bacterial infection is an intracellular bacterial infection.

30. 27. The use of claim 26, wherein the subject is a human.

31. 27. The use of claim 26, wherein the treatment further comprises administering a second therapeutic agent, wherein the second therapeutic agent is a second antibiotic selected from an aminoglycoside, a beta-lactam, a macrolide, a cyclic peptide, a tetracycline, a fluoroquinoline, a fluoroquinolone, and an oxazolidinone.

32. 27. The use of claim 26, wherein the antibody drug conjugate is administered to the subject orally, topically, nasally, intravenously, intramuscularly, or subcutaneously.

33. 10. Use of a compound of claim 1 in the preparation of a medicament for preventing or treating cellulitis, bacteremia, skin necrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boils, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, post-burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, septic arthritis, mastitis, prosthetic joint-related infection, catheter-related infection, or implant-related infection in a subject.

34. 10. A pharmaceutical composition comprising the compound of claim 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

35. 5. A pharmaceutical dosage form comprising the compound of claim 4 or a pharmaceutically acceptable salt thereof.

36. An antibody drug conjugate comprising an antibody or antigen-binding fragment thereof conjugated to the compound of claim 4 via a linker or linker-spacer.

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