Antibiotic against disease-causing bacteria

Abstract

The disclosure provides, among other things, compounds useful for treating a disease, disorder, and / or infection, as well as pharmaceutical compositions containing such compounds.

Description

PATENT Attorney Docket No. 121504-5016-WO ANTIBIOTIC AGAINST DISEASE-CAUSING BACTERIACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of and priority to U.S. Provisional Application Nos.63 / 769,629, filed on March 10, 2025, and 63 / 908,910, filed on October 31, 2025, which are each incorporated herein by reference in their entireties.FIELD OF THE INVENTION

[0002] The disclosure relates generally to compounds for use as antibiotics, and methods of using such compounds as treatment for a disease, disorder, and / or infection.BACKGROUND OF THE INVENTION

[0003] Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has emerged as a major public health concern of the 21st century. Therefore, novel antibiotics are needed to treat diseases, disorders, and / or infections associated with bacteria.SUMMARY OF THE INVENTION

[0004] Disclosed herein are Formibactin A and analogs thereof and / or prodrugs thereof to treat a disease, disorder, and / or infection without significantly disrupting the gut microbiome. In some embodiments, the disease, disorder, and / or infection is associated with a pathogen, such as an oral disease-associated pathogen, a bacterial vaginosis (BV)-associated pathogen, an endometriosis-associated pathogen, an oncogenic bacterium, a colorectal cancer (CRC)- associated pathogen, gastric cancer-associated pathogen, a gastritis-associated pathogen, a Lyme disease-associated pathogen, an episodic fever-associated pathogen, a relapsing fever (RF)- associated pathogen, gonorrhea-associated pathogen, or a syphilis-associated pathogen.

[0005] In one aspect, the disclosure provides a method of treating a patient infected with a bacterium, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (La):DB1 / 167011927.11or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, - C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C > alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.DB1 / 167011927.11

[0006] In one aspect, the disclosure provides a method of treating a disease or disorder associated with an infection with a bacterium in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I-a).

[0007] In one aspect, the disclosure provides a method of treating a disease or disorder selected from acute bacterial sinusitis, acute otitis media, an anaerobic infection, bacteremia, bacterial vaginosis, cancer, cellulitis, chorioamnionitis, colitis, COPD exacerbations, dental caries, diarrhea, endocarditis, endometriosis, episodic fever, food poisoning, gas gangrene, gonorrhea, hemolytic uremic syndrome, impetigo, intra-abdominal abscess, intra-abdominal infections, Lemierre’s syndrome, Lyme disease, Lyme neuroborreliosis, maternal peripartum infections, meningitis, myonecrosis, neonatal early-onset sepsis, nongonococcal urethritis, odontogenic infections, opportunistic infections, osteomyelitis, pelvic inflammatory disease, peptic ulcer disease, peptoanaerobacter stomatis, periodontitis, peritonitis, pneumonia , purulent pericarditis, relapsing fever, sepsis, soft tick relapsing fever, syphilis, toxic shock syndrome, and urinary tract infection, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I-a).

[0008] In one aspect, the disclosure provides a method of increasing efficacy of chemotherapy, radiotherapy, and / or immunotherapy treatment, comprising administering to a subject a therapeutically effective amount of a compound of Formula (I-a).

[0009] In one aspect, the disclosure provides a method of preventing plaque buildup or atherosclerosis, comprising administering to a subject a therapeutically effective amount of a compound of Formula (I-a).

[0010] In one aspect, the disclosure provides a coating for hospital equipment comprising a compound of Formula (I-a).

[0011] In one aspect, the disclosure provides a compound of Formula (IV-b):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, or cocrystal thereof, wherein in Formula (IV-b):DB1 / 167011927.11R1is selected from -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R2is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, and 5; andy is an integer of 1 or 2.BRIEF DESCRIPTION OF THE FIGURES

[0012] Figure 1 shows animal efficacy of ADC238. The efficacy of ADC238 and control antibiotic Doxycycline against a murine infection with B. burgdorferi . C3H mice were infected intradermally (106CFU) with B. burgdorferi VfiaB-luc (a constitutively expressed, codon optimized firefly luciferase); and after 3 weeks were treated for 4 days with ADC238 and Doxycycline via oral gavage. All mice were treated once a day and the total daily doseDBl / 167011927.11(mg / kg / day) is indicated. For each time point, the presence of B. burgdorferi cells was observed with D-luciferin and imaged by IVIS™ Spectrum 2 In Vivo Imaging System.

[0013] Figures 2A-2C show 3D tumor spheroids models for testing anti-CRC antimicrobials. Figure 2A shows cultured HCT116 cell spheroid was stained by CellTracker™ Blue CMAC Dye (blue) without GFP expressing F. nucleatum (green) cocultured with HCT116. Scale bar is 100 pm. Figures 2B-2C show tumor spheroids containing F. nucleatum were treated with 10*MIC of ADC238 for 24 h and then bacterial burden from spheroids were determined by treating spheroids by AccuMax™ and plated on Colombia blood agar plates to enumerate F. nucleatum. *p<0.05 (two-way ANOVA ort-test).

[0014] Figure 3 shows synthetic schemes for preparing exemplary prodrugs of ADC238, Compounds 1002 (“Prodrug- 1”), 1003 (“Prodrug-2”), 1004 (“Prodrug-3”), and 1005 (“Prodrug- 4”).

[0015] Figures 4A and 4B show the efficacy of ADC238 in a murine Lyme borreliosis model. Figure 4A shows the quantification of B. burgdorferi in tissues (ear and muscle) of animals. Figure 4B shows the percentage of mice from which cultures were positive for B. burgdorferi in the murine Lyme borreliosis model.DETAILED DESCRIPTION OF THE INVENTIONDefinitions and Abbreviations

[0016] As used herein, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, reference to “an active agent” includes a single active agent as well as two or more different active agents in combination. It is to be understood that present teaching is not limited to the specific dosage forms, carriers, or the like, disclosed herein and as such may vary.

[0017] The abbreviations used herein generally have their conventional meaning within the chemical and biological arts.

[0018] “Compound of the invention,” as used herein refers to the compounds discussed herein, salts (e.g. pharmaceutically acceptable salts), solvates, tautomers, isomers, hydrates, cocrystals, and prodrugs of these compounds.DB1 / 167011927.11

[0019] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents, which would result from writing the structure from right to left, e.g., -CH2O- is intended to also recite - OCH2-.

[0020] The term “poly” as used herein means at least 2. For example, a polyvalent metal ion is a metal ion having a valency of at least 2.

[0021] “Moiety” refers to a radical of a molecule that is attached to the remainder of the molecule.

[0022] The symbol ux / w' , whether utilized as a bond or displayed perpendicular to a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule.

[0023] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons). In some embodiments, the term “alkyl” means a straight or branched chain, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclobutyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, homologs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0024] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by -CH2CH2CH2CH2-, and further includes those groups described below as “heteroalkylene.” Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.DB1 / 167011927.11

[0025] The term “alkenylene” by itself or as part of another substituent means a divalent radical derived from an alkene.

[0026] The term “cycloalkylene” by itself or as part of another substituent means a divalent radical derived from a cycloalkane.

[0027] The term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from an heteroalkane.

[0028] The term “heterocycloalkylene” by itself or as part of another substituent means a divalent radical derived from an heterocycloalkane.

[0029] The term “arylene” by itself or as part of another substituent means a divalent radical derived from an aryl.

[0030] The term “heteroarylene” by itself or as part of another substituent means a divalent radical derived from heteroaryl.

[0031] The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

[0032] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom. In some embodiments, the term “heteroalkyl,” by itself or in combination with another term, means a stable straight or branched chain, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom. In an exemplary embodiment, the heteroatoms can be selected from the group consisting of B, O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) B, O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to,-0-CH3, -CH2-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-CH2-CH2- N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive,DB1 / 167011927.11such as, for example, -CH2-NH-OCH3. Similarly, the term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O)2R’- represents both -C(O)2R’- and -R’C(O)2-.

[0033] The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 2-(4-methylpiperazin-l- yl)ethyl, 3-(4-methylpiperazin-l-yl)propyl, 2-morpholinoethyl, 3 -morpholinopropyl, 1- methylazetidin-3-yl, 1-ethylazeti din-3 -yl, l-isopropylazetidin-3-yl, l-methylpiperidin-4-yl, 1- ethylpiperidin-4-yl or, l-isopropylpiperidin-4-yl, 1 -(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran- 3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.

[0034] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C4)alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl , 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl, 3 -bromopropyl, and the like.

[0035] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 or 2 or 3 rings), which are fused together or linked covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms. In an exemplary embodiment, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogenDB1 / 167011927.11atom(s) are optionally quatemized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2 -furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0036] For brevity, the term “aryl” when used in combination with other terms (e.g, aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3 -(1 -naphthyloxy )propyl, and the like).

[0037] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and “heteroaryl”) are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0038] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generically referred to as “alkyl group substituents,” and they can be one or more of a variety of groups selected from, but not limited to: -R’, -OR’, =0, =NR’, =N-0R’, -NR’R”, -SR’, -halogen, -SiR’R”R’”, -OC(O)R’, -C(O)R’, -CO2R’, -CONR’R”, -0C(0)NR’R”, -NR”C(O)R’, -NR’-C(O)NR”R’”, -NR”C(O)2R’,-NR’” ”-C(NR’R’R ”)=NR”“, -NR ’ ”-C(NR’R”)=NR’”, -S(O)R’, -S(O)2R’,-S(O)2NR’R”, -NR”SO2R’, -CN, -NO2, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci- C4)alkyl, in a number ranging from zero to (2m’+l), where m’ is the total number of carbon atoms in such radical. R’, R”, R’”, R”” and R’”” each preferably independently refer to hydrogen, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, e.g., arylDB1 / 167011927.11substituted with 1-3 halogens, substituted or un substituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R’, R”, R’”, R”” and R’”” groups when more than one of these groups is present. When R’ and R” are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR’R” is meant to include, but not be limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3and -CH2CF3) and acyl (e. , -C(O)CH3, - C(O)CF3, -C(O)CH2OCH3, and the like).

[0039] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are generically referred to as “aryl group substituents.” The substituents are selected from, for example: -R’, -OR’, =0, =NR’, =N-0R’, -NR’R”, -SR’, -halogen, -SiR’R”R’”, -OC(O)R’, -C(O)R’, -CO2R’, -CONR’R”, -0C(0)NR’R”,-NR”C(0)R’, -NR’-C(0)NR”R”’, -NR”C(O)2R’,-NR”“’-C(NR’R”R’”)=NR”“, -NR”“-C(NR’R”)=NR’”, -S(O)R’, -S(O)2R’, - S(O)2NR’R”, -NR”SO2R’, -CN, -NO2, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci- C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R’, R”, R’”, R”“ and R”“’ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R’, R”, R’”, R”“ and R”“’ groups when more than one of these groups is present.

[0040] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CRR’)q-U-, wherein T and U are independently -NR-, -O-, -CRR’- or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula-A-(CH2)r-B-, wherein A and B are independently -CRR’-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, - S(O)2NR’- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the DB1 / 167011927.11new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR’)s-X-(CR”R”’)d-, where s and d are independently integers of from 0 to 3, and X is -O-, -NR’-, -S-, -S(O)-, -S(O)2-, or-S(O)2NR’-. The substituents R, R’, R” and R’” are preferably independently selected from hydrogen or substituted or unsubstituted Ci or C2 or C3 or C4 or C5 or Ce alkyl.

[0041] “Ring” as used herein, means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. A ring includes fused ring moieties. The number of atoms in a ring is typically defined by the number of members in the ring. For example, a “5- to 7-membered ring” means there are 5 or 6 or 7 atoms in the encircling arrangement. Unless otherwise specified, the ring optionally includes a heteroatom. Thus, the term “5 to 7-membered ring” or “5 or 6 or 7 membered ring” includes, for example phenyl, pyridinyl and piperidinyl. The term “5 to 7- membered heterocycloalkyl ring” “5 or 6 or 7-membered heterocycloalkyl ring”, on the other hand, would include pyridinyl and piperidinyl, but not phenyl. The term “ring” further includes a ring system comprising more than one “ring”, wherein each “ring” is independently defined as above.

[0042] As used herein, the term “heteroatom” includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur (S), silicon (Si), germanium (Ge), and aluminum (Al).

[0043] The term “leaving group” means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include triflate, chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

[0044] The symbol “R” is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl groups.DB1 / 167011927.11

[0045] By “effective” amount of a drug, formulation, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect. A “Topically effective,” “pharmaceutically effective,” or “therapeutically effective” amount refers to the amount of drug needed to effect the desired therapeutic result.

[0046] The term “pharmaceutically acceptable salt” includes physiologically acceptable acid addition salts of the compounds disclosed herein, for example, hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. Salts may also be formed with bases, for example, sodium, potassium, magnesium, and calcium salts.

[0047] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0048] Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms.

[0049] Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the invention. The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included.

[0050] Compounds of the invention can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis- and trans- somers, (-)- and (+)- enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically DB1 / 167011927.11enriched mixtures, as falling within the scope of the invention. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0051] Optically active (R)- and (5)-isomers and d and I isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0052] The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.

[0053] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable vehicle” refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of an active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient. Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their formulation is well known to those in the art of cosmetics and topical pharmaceuticals. Additional information concerning carriers can be foundDB1 / 167011927.11in Remington: The Science and Practice of Pharmacy, 21 st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference.

[0054] The term “pharmaceutically acceptable additive” refers to preservatives, antioxidants, fragrances, emulsifiers, dyes and excipients known or used in the field of drug formulation and that do not unduly interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient. Additives for topical formulations are well-known in the art, and may be added to the topical composition, as long as they are pharmaceutically acceptable and not deleterious to the epithelial cells or their function. Further, they should not cause deterioration in the stability of the composition. For example, inert fillers, anti -irritants, tackifiers, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactant, emollients, coloring agents, preservatives, buffering agents, other permeation enhancers, and other conventional components of topical or transdermal delivery formulations as are known in the art.

[0055] The term “excipients” is conventionally known to mean carriers, diluents and / or vehicles used in formulating drug compositions effective for the desired use.

[0056] The terms “effective amount” or a “therapeutically effective amount” of a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to provide the desired effect. In the oral dosage forms of the present disclosure, an “effective amount” of one active of the combination is the amount of that active that is effective to provide the desired effect when used in combination with the other active of the combination. The amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0057] The phrases “active ingredient”, “therapeutic agent”, “active”, or “active agent” mean a chemical entity which can be effective in treating a targeted disorder, disease or condition.

[0058] The phrase “pharmaceutically acceptable” means moieties or compounds that are, within the scope of medical judgment, suitable for use in humans without causing undesirable biological effects such as undue toxicity, irritation, allergic response, and the like, for example.DB1 / 167011927.11

[0059] The phrase “oral dosage form” means any pharmaceutical formulation administered to a subject via the oral cavity. Exemplary oral dosage forms include tablets, capsules, films, powders, sachets, granules, solutions, solids, suspensions or as more than one distinct unit (e.g., granules, tablets, and / or capsules containing different actives) packaged together for coadministration, and other formulations known in the art. An oral dosage form can be one, two, three, four, five or six units. When the oral dosage form has multiple units, all of the units are contained within a single package, (e.g. a bottle or other form of packaging such as a blister pack). When the oral dosage form is a single unit, it may or may not be in a single package. In a preferred embodiment, the oral dosage form is one, two or three units. In a particularly preferred embodiment, the oral dosage form is one unit.

[0060] The phrase “unit”, as used herein, refers to the number of discrete objects to be administered which comprise the dosage form. In some embodiments, the dosage form includes a compound of the invention in one capsule. This is a single unit. In some embodiments, the dosage form includes a compound of the invention as part of a therapeutically effective dosage of a cream or ointment. This is also a single unit. In some embodiments, the dosage form includes a compound of the invention and another active ingredient contained within one capsule, or as part of a therapeutically effective dosage of a cream or ointment. This is a single unit, whether or not the interior of the capsule includes multiple discrete granules of the active ingredient. In some embodiments, the dosage form includes a compound of the invention in one capsule, and the active ingredient in a second capsule. This is a two unit dosage form, such as two capsules or tablets, and so such units are contained in a single package. Thus the term ‘unit’ refers to the object which is administered to the animal, not to the interior components of the object.

[0061] “Biological medium,” as used herein refers to both in vitro and in vivo biological milieus. Exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.

[0062] “Inhibiting” is used herein to refer to the partial or full blockade of the growth of a bacterium described herein.DB1 / 167011927.11

[0063] As used herein, the terms “treat,” “treatment,” and / or “treating” may refer to the management of a disease, disorder, pathological condition, infection, or symptom thereof with the intent to cure, ameliorate, stabilize, and / or control the disease, disorder, pathological condition, infection, or symptom thereof. Regarding control of the disease, disorder, infection, or pathological condition more specifically, “control” may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition). As used herein, the terms “prevent,” “preventing,” and / or “prevention” may refer to reducing the risk of developing a disease, disorder, infection, or pathological condition.

[0064] As used herein, a “disease or disorder associated with a bacterium”, “disease or disorder associated with an infection with a bacterium”, and / or “disease or disorder associated with an infection” means a disease or disorder that is caused by, co occurs with, correlates with, is present in conjunction with, is exacerbated by, is indicative of, or is otherwise linked to the referenced bacterium. In some embodiments, the disease or disorder is caused by the bacterium (i.e., the bacterium is the direct or proximate cause of the disease or disorder). In some embodiments, the bacterium is the sole cause of the disease or disorder. In other embodiments, the bacterium is one of several causes of the disease or disorder.

[0065] Embodiments of the invention also encompass compounds that are poly- or multi -valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of use in the invention or reactive analogues thereof.

[0066] In general, as used herein, the term “substantially” means ±10%, and in some embodiments, ±5%. In addition, reference throughout this specification to “one example,” “an example,” “one embodiment,” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the example is included in at least one example of the present technology. Thus, the occurrences of the phrases “in one example,” “in an example,” “one embodiment,” or “an embodiment” in various places throughout this specification are not necessarily all referring to the same example. Furthermore, the particular features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or moreDB1 / 167011927.11examples of the technology. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology.CompoundsCompounds of Formula (I -a)

[0067] In one aspect, the disclosure provides a compound of Formula (I-a):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, - C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Cs-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cx-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;DBl / 167011927.11y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

[0068] In some embodiments, X1is a moiety comprising one or more groups selected from - C(O)-, -C(O)NH-, and optionally substituted C1-C4 alkylene. In an exemplary embodiment, X1which:R3is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6; andy is an integer of 1 or 2.

[0069] In some embodiments, the compound of Formula (I-a) has a structure according to Formula (Il-a):DB1 / 167011927.11wherein in Formula (Il-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, - C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Ca- cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R3is selected from H, -ORa, -C(O)Ra, -C(O)ORa, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl;X2is a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, - C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andDBl / 167011927.11ringB is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

[0070] In some embodiments, X2is optionally substituted C1-C4 alkylene. In an exemplary embodiment, X2is optionally substituted C1-C2 alkylene.

[0071] In some embodiments, ring A is optionally substituted 3- to 8-memberedheterocycloalkylene. In an exemplary embodiment, ring A isoptionally substituted.

[0072] In some embodiments, ring B is an optionally substituted 3- to 8-membered aryl ring fused to an optionally substituted 3- to 8-membered heterocycloalkyl ring. In an exemplaryembodiment, ring B isand ring B is optionally substituted.

[0073] In some embodiments, the compound of Formula (I-a) and / or Formula (Il-a) has a structure according to Formula (Ill-a):wherein in Formula (Ill-a):R1and R2are independently at each occurrence selected from H, -(CH2)xORa, - (CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, - C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3- cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R3is selected from H, -ORa, -C(O)Ra, -C(O)ORa, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl; DBl / 167011927.11R4, R5, R6, R7, R8, R9, R10, R11, and R12are independently at each occurrence selected from H, halogen, -ORa, -N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, and 5; andy is an integer of 1 or 2.

[0074] In some embodiments, R3is Ci-Ce alkyl. In an exemplary embodiment, R3is t-butyl.

[0075] In some embodiments, one or more of R4, R5, R6, R7, R8, R9, R10, R11, and R12are H. In an exemplary embodiment, R8is H. In an exemplary embodiment, R4, R5, R6, R7, R9, R10, R11, and R12are H.

[0076] In some embodiments, the compound of Formula (I-a), Formula (IT-a), and / or Formula (Ill-a) has a structure according to Formula (IV-a):wherein in Formula (IV-a):R1is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionallyDBl / 167011927.11substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R2is selected from H, -(CH2)xORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Cs haloalkyl, optionally substituted C -Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, and 5; andy is an integer of 1 or 2.

[0077] In some embodiments, wherein R1is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, - C(O)Ra, -C(O)ORa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-C6alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ce-Cio aryl, and x is selected from 0, 1, 2, 3, and 4. In some embodiments, R1is selected from H,DBl / 167011927.11exemplary embodiment, R1is H. In an exemplary embodiment, R1is not H.

[0078] In some embodiments, R2is -(CH2)x-(Cs-C6 cycloalkyl), and x is selected from 1, 2, 3, and 4. In an exemplary embodiment, R2is -(CH2)-(cyclopentyl).

[0079] In some embodiments, R2is Ci-Ce alkyl. In an exemplary embodiment, R2is 1-butyl.

[0080] In one aspect, the compound of Formula (I-a), Formula (Il-a), Formula (Ill-a), and / or Formula (IV-a) is selected from any one of Compounds 101-136:DBl / 167011927.11DB1 / 167011927.11DB1 / 167011927.11DB1 / 167011927.11

[0081] In some embodiments, the compound of Formula (I-a), Formula (Il-a), Formula (Ill-a), and / or Formula (IV-a) has the structure of Compound 1001 or Compound 1019:Compound 1019.

[0082] Compound 1001 is also referred to as “Formibactin A”, “BB-83698”, and “ADC238”. Compound 1019 is also referred to as “BB-81384” and “ADC238-1.”

[0083] In some embodiments, the compound of Formula (I-a), Formula (Il-a), Formula (Ill-a), and / or Formula (IV-a) is selected from any one of Compounds 1002-1018 and 1020-1036:Compound 1002DBl / 167011927.11Compound 1005Compound 1006DBl / 167011927.11Compound 1010DBl / 167011927.11Compound 1014DBl / 167011927.11Compound 1017DBl / 167011927.11Compound 1022DBl / 167011927.11Compound 1026DBl / 167011927.11Compound 1031DBl / 167011927.11DB1 / 167011927.11Compound 1036.Compounds of Formula (I-b)

[0084] In one aspect, the disclosure provides a compound of Formula (I-b):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, or cocrystal thereof, wherein in Formula (I-b):R1is selected from -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C'3-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R2is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally DBl / 167011927.11substituted C2-Cg alkenylene, optionally substituted C2-Ce alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

[0085] In some embodiments, X1is a moiety comprising one or more groups selected from - C(O)-, -C(O)NH-, and optionally substituted C1-C4 alkylene. In an exemplary embodiment, X1which:R3is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted CI-CG alkyl, optionally substituted C2-Cr> alkenyl, optionally substituted C2-C6DB1 / 167011927.11alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6; andy is an integer of 1 or 2.

[0086] In some embodiments, the compound of Formula (I-b) has a structure according to Formula (Il-b):wherein in Formula (Il-b):R1is selected from -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C'3-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R2is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R3is selected from H, -ORa, -C(O)Ra, -C(O)ORa, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl;DBl / 167011927.11X2is a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, - C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

[0087] In some embodiments, X2is optionally substituted C1-C4 alkylene. In an exemplary embodiment, X2is optionally substituted C1-C2 alkylene.

[0088] In some embodiments, ring A is optionally substituted 3- to 8-memberedheterocycloalkylene. In an exemplary embodiment, ring A isand ring A is optionally substituted.

[0089] In some embodiments, ring B is an optionally substituted 3- to 8-membered aryl ring fused to an optionally substituted 3- to 8-membered heterocycloalkyl ring. In an exemplaryembodiment, ring B isand ring B is optionally substituted.DBl / 167011927.11

[0090] In some embodiments, compound of Formula (I-b) and / or Formula (TF-b) has a structure according to Formula (Ill-b):wherein in Formula (Ill-b):R1is selected from -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C'3-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R2is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R3is selected from H, -ORa, -C(O)Ra, -C(O)ORa, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl;R4, R\ R6, R7, R8, R9, R10, R11, and R12are independently at each occurrence selected from H, halogen, -ORa, -N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered DBl / 167011927.11heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, and 5; andy is an integer of 1 or 2.

[0091] In some embodiments, R3is Ci-Ce alkyl. In an exemplary embodiment, R3is t-butyl.

[0092] In some embodiments, one or more of R4, R5, R6, R7, R8, R9, R10, R11, and R12are H. In an exemplary embodiment, wherein R8is H. In an exemplary embodiment, R4, R5, R6, R7, R9, R10, R11, and R12are H.

[0093] In some embodiments, the compound of Formula (I-b), Formula (Il-b), and / or Formula (Ill-b) has a structure according to Formula (IV-b):wherein in Formula (IV-b):R1is selected from -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R2is selected from H, -(CH2)xORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ca-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted Cb-Ce alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionallyDB1 / 167011927.11substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, and 5; andy is an integer of 1 or 2.

[0094] In some embodiments, R1is selected from -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, - C(O)ORa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ce-Cio aryl, and x is selected from 0, 1, 2, 3, and 4. In an exemplary embodiment, R1is selected from

[0095] In some embodiments, R2is -(CH2)x-(C3-Ce cycloalkyl), and x is selected from 1, 2, 3, and 4. In an exemplary embodiment, R2is -(CH2)-(cyclopentyl).

[0096] In some embodiments, R2is C1-C6 alkyl. In an exemplary embodiment, R2is 1-butyl.

[0097] In some aspects, the disclosure provides a compound of Formula (IV-b):DBl / 167011927.11R2is -(CH2)-(cyclopentyl) or 1 -butyl.

[0098] In some embodiments, the compound of Formula (I-b), Formula (Il-b), Formula (Ill-b), and / or (IV-b) is selected from any one of Compounds 102-118 and 120-136.

[0099] In some embodiments, the compound of Formula (I-b), Formula (Il-b), Formula (Ill-b), and / or Formula (IV-b) is selected from any one of Compounds 1002-1018 and 1020-1036.

[0100] In some embodiments, the compound of Formula (1-a), Formula (11-a), Formula (111-a), Formula (IV-a), Formula (I-b), Formula (Il-b), Formula (Ill-b), and / or Formula (IV-b) inhibits the activity of the PDF enzyme. In some embodiments, Compound 1001 inhibits the activity of the PDF enzyme. In some embodiments, Compound 1019 inhibits the activity of the PDF DBl / 167011927.11enzyme. In some embodiments, a compound selected from any one of Compounds 101-136 inhibits the activity of the PDF enzyme. In some embodiments, a compound selected from any one of Compounds 1002-1018 and 1020-1036 inhibits the activity of the PDF enzyme.

[0101] In some embodiments, the compound of Formula (I-a), Formula (Il-a), Formula (Ill-a), Formula (IV-a), Formula (I-b), Formula (Il-b), Formula (Ill-b), and / or Formula (IV-b) exhibits antibacterial activity against a pathogen. In some embodiments, Compound 1001 exhibits antibacterial activity against a pathogen. In some embodiments, Compound 1019 exhibits antibacterial activity against a pathogen. In some embodiments, a compound selected from any one of Compounds 101-136 exhibits antibacterial activity against a pathogen. In some embodiments, a compound selected from any one of Compounds 1002-1018 and 1020-1036 exhibits antibacterial activity against a pathogen.[00102J In some embodiments, the compound of Formula (1-a), Formula (11-a), Formula (111-a), Formula (IV-a), Formula (I-b), Formula (Il-b), Formula (Ill-b), Formula (IV-b), Compounds 101- 136, Compound 1001, Compound 1019, Compounds 1002-1018, or Compounds 1020-1036 have a minimum inhibitory concentration (MIC) of less than or equal to about 64 pg / ml, less than or equal to about 60 pg / ml, less than or equal to about 55 pg / ml, less than or equal to about 50 pg / ml, less than or equal to about 45 pg / ml, less than or equal to about 40 pg / ml, less than or equal to about 35 pg / ml, less than or equal to about 30 pg / ml, less than or equal to about 25 pg / ml, less than or equal to about 20 pg / ml, less than or equal to about 15 pg / ml, less than or equal to about 10 pg / ml, less than or equal to about 9 pg / ml, less than or equal to about 8 pg / ml, less than or equal to about 7 pg / ml, less than or equal to about 6 pg / ml, less than or equal to about 5 pg / ml, less than or equal to about 4 pg / ml, less than or equal to about 3 pg / ml, less than or equal to about 2 pg / ml, less than or equal to about 1 pg / ml, less than or equal to about 0.9 pg / ml, less than or equal to about 0.8 pg / ml, less than or equal to about 0.7 pg / ml, less than or equal to about 0.6 pg / ml, less than or equal to about 0.5 pg / ml, less than or equal to about 0.4 pg / ml, less than or equal to about 0.3 pg / ml, less than or equal to about 0.2 pg / ml, less than or equal to about 0.1 pg / ml, less than or equal to about 0.09 pg / ml, less than or equal to about 0.08 pg / ml, less than or equal to about 0.07 pg / ml, less than or equal to about 0.06 pg / ml, less than or equal to about 0.05 pg / ml, less than or equal to about 0.04 pg / ml, less than or equal to about 0.03DB1 / 167011927.11pg / ml, less than or equal to about 0.02 pg / ml, less than or equal to about 0.01 pg / ml, less than or equal to about 0.005 pg / ml, or less than or equal to about 0.001 pg / ml.

[0103] In some embodiments, the compound of Formula (I-a), Formula (Il-a), Formula (Ill-a), Formula (IV-a), Formula (I-b), Formula (Il-b), Formula (Ill-b), Formula (IV-b), Compounds 101- 136, Compound 1001, Compound 1019, Compounds 1002-1018, or Compounds 1020-1036 are not or are substantially not cytotoxic to mammalian cells. In some embodiments, the term “not or are substantially not cytotoxic to mammalian cells” refers to an IC50 value of the compound described herein in a mammalian cell of greater than about 50 pg / ml or greater than about 100 pg / ml.Pharmaceutical Compositions

[0104] In one aspect, the disclosure provides a pharmaceutical composition comprising the compound described herein. In an exemplary embodiment, the pharmaceutical composition comprises a compound of Formula (I-a). In an exemplary embodiment, the pharmaceutical composition comprises a compound of Formula (Il-a). In an exemplary embodiment, the pharmaceutical composition comprises a compound of Formula (IILa). In an exemplary embodiment, the pharmaceutical composition comprises a compound of Formula (IV-a). In an exemplary embodiment, the pharmaceutical composition comprises a compound of Formula (I- b). In an exemplary embodiment, the pharmaceutical composition comprises a compound of Formula (Il-b). In an exemplary embodiment, the pharmaceutical composition comprises a compound of Formula (Ill-b). In an exemplary embodiment, the pharmaceutical composition comprises a compound of Formula (IV-b). In an exemplary embodiment, the pharmaceutical composition comprises Compound 1001. In an exemplary embodiment, the pharmaceutical composition comprises Compound 1019. In an exemplary embodiment, the pharmaceutical composition comprises a compound selected from Compounds 101-136. In an exemplary embodiment, the pharmaceutical composition comprises a compound selected from Compounds 1002-1018 and 1020-1036.

[0105] In some embodiments, the pharmaceutically acceptable composition comprises at least one pharmaceutically acceptable carrier, excipient, and / or diluent.DB1 / 167011927.11

[0106] In an exemplary embodiment, the compound described herein is present in the pharmaceutical formulation in an amount of between about 0.0001% to about 60% (w / w). In an exemplary embodiment, the amount is between about 0.01% to about 10% (w / w). In an exemplary embodiment, the amount is between about 0.1% to about 10% (w / w). In an exemplary embodiment, the amount is between about 0.25% to about 6% (w / w). In an exemplary embodiment, the amount is between about 0.5% to about 5% (w / w). In an exemplary embodiment, the amount is between about 0.1% and about 1.0% (w / w). In an exemplary embodiment, the amount is between about 1.0% and about 2.0% (w / w). In an exemplary embodiment, the amount is between about 2.0% and about 3.0% (w / w). In an exemplary embodiment, the amount is between about 3.0% and about 4.0% (w / w). In an exemplary embodiment, the amount is between about 4.0% and about 5.0% (w / w).

[0107] The pharmaceutical compositions disclosed herein can take a variety of forms adapted to the chosen route of administration. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutical formulations incorporating the compounds described herein. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, propylene glycol, mineral oil, vegetable oil and dimethylsulfoxide (DMSO).

[0108] The pharmaceutical compositions disclosed herein may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. It is further understood that the best method of administration may be a combination of methods. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques.

[0109] The pharmaceutical compositions containing compounds disclosed herein are preferably in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.DBl / 167011927.11

[0110] Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia; lubricating agents, for example magnesium stearate, stearic acid or talc; and extenders and bulking agents, such as microcrystalline cellulose. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[0111] Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0112] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents, which may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may alsoDB1 / 167011927.11contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0113] Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0114] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other dispersing agents include hydrophilic polymers, electrolytes, TweenTM 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as PlasdoneTM), and the carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC KI OOM), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer (PlasdoneTM, e.g., S-630), 4-(l, 1,3,3- tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68TM, F88TM, and F108TM, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 9080, also known as Poloxamine 9080, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)). Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.DB1 / 167011927.11

[0115] The pharmaceutical compositions provided herein may also be in the form of oil-in- water emulsions and water-in-oil emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth; naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol; anhydrides, for example sorbitan monooleate; and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0116] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0117] In some embodiments, the pharmaceutical compositions provided herein provide for topical application of the compounds described herein. Topical administration includes for example, transmucosal, transdermal, ungual and transungual routes of administration. The topical compositions useful in the subject invention can be made into a wide variety of product types. These include, but are not limited to, lotions, creams, gels, sticks, sprays, ointments, pastes, foams, mousses, masks, eye ointments, eye or ear drops, impregnated dressings, wipes, cleansers including soaps, body washes and shampoos, and make-up products, such as bases, blushes, lipsticks, and eye shadows, among others. These product types can comprise several types of carrier systems including, but not limited to particles, nanoparticles, and liposomes. IfDB1 / 167011927.11desired, disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. Techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy, supra. The formulation can be selected to maximize delivery to a desired target site in the body. The formulations can also include various conventional colorants, fragrances, thickeners, preservatives, humectants, emollients, demulcents, solubilizing excipients, dispersants, penetration enhancers, plasticizing agents, preservatives, stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers, moisturizers, astringents, deodorants, and the like, which can be added to provide additional benefits such as, for example, improving the feel and / or appearance of the topical preparation.

[0118] The pharmaceutical composition described herein may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0119] Alternatively, the pharmaceutical compositions can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

[0120] For administration to non-human animals, the composition containing the therapeutic compound may be added to the animal’s feed or drinking water. Also, it will be convenient to formulate animal feed and drinking water products so that the animal takes in an appropriate quantity of the compound in its diet. It will further be convenient to present the compound in a composition as a premix for addition to the feed or drinking water. The composition can also be added as a food or drink supplement for humans.

[0121] Dosage levels of the order of from about 5 mg to about 250 mg per kilogram of body weight per day and more preferably from about 25 mg to about 150 mg per kilogram of body weight per day, are useful in the treatment of the indicated conditions described herein. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the condition being treated and the particular mode of DB1 / 167011927.11administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.

[0122] Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0123] Preferred compounds of the invention will have desirable pharmacological properties that include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.

[0124] The amount of the pharmaceutical composition required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.

[0125] In an exemplary embodiment, the pharmaceutical composition described herein includes an additional active ingredient. In another exemplary embodiment, the additional active ingredient is a compound that has been approved for human use by the United States Food and Drug Administration.Coatings

[0126] In one aspect, the disclosure provides coating for hospital equipment comprising a compound described herein. In an exemplary embodiment, the compound has a structure according to Formula (I-a). In an exemplary embodiment, the compound has a structure according to Formula (Il-a). In an exemplary embodiment, the compound has a structure according to Formula (Ill-a). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structureDB1 / 167011927.11according to Formula (I-b). In an exemplary embodiment, the compound has a structure according to Formula (Il-b). In an exemplary embodiment, the compound has a structure according to Formula (Ill-b). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001. In an exemplary embodiment, the compound is Compound 1019. In an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.

[0127] In some embodiments, the hospital equipment is a medical device. In an exemplary embodiment, the hospital equipment is a catheter.

[0128] In some embodiments, the coating comprises a polymer matrix containing the compound. In some embodiments, the polymer matrix comprises a polymer selected from polyurethane, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethyl ene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, and combinations thereof. In some embodiments, the polymer matrix comprises a polymer selected from a polyurethane, cellulose or a cellulose-derived polymer (e.g., nitrocellulose), or a combination of polyurethane and cellulose or a cellulose-derived polymer.

[0129] In some embodiments, the coating is a sustained release coating. In an exemplary embodiment, the coating comprises a polymer wherein the agent is released from a polymer matrix on the medical device (e.g. catheter).DB1 / 167011927.11

[0130] In some embodiments, the coating reduces or prevents biofilm formation. In some embodiments, the coating prevents or reduces medical device-associated infections.Methods and Uses

[0131] In one aspect, the disclosure provides a method of treating a patient infected with a bacterium, the method comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein. In an exemplary embodiment, the compound has a structure according to Formula (I-a). In an exemplary embodiment, the compound has a structure according to Formula (Il-a). In an exemplary embodiment, the compound has a structure according to Formula (Ill-a). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structure according to Formula (I-b). In an exemplary embodiment, the compound has a structure according to Formula (Il-b). In an exemplary embodiment, the compound has a structure according to Formula (Ill-b). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001. In an exemplary embodiment, the compound is Compound 1019. In an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.

[0132] In one aspect, the disclosure provides a method of treating an infection in a patient, wherein the infection is with a bacterium, the method comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein. In an exemplary embodiment, the compound has a structure according to Formula (I-a). In an exemplary embodiment, the compound has a structure according to Formula (Il-a). In an exemplary embodiment, the compound has a structure according to Formula (Ill-a). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structure according to Formula (I-b). In an exemplary embodiment, the compound has a structure according to Formula (Il-b). In an exemplary embodiment, the compound has a structure according to Formula (Ill-b). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001.DB1 / 167011927.11In an exemplary embodiment, the compound is Compound 1019. Tn an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.

[0133] In one aspect, the disclosure provides a method of treating a disease or disorder associated with an infection with a bacterium in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein. In an exemplary embodiment, the compound has a structure according to Formula (I-a). In an exemplary embodiment, the compound has a structure according to Formula (Il-a). In an exemplary embodiment, the compound has a structure according to Formula (Ill-a). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structure according to Formula (I-b). In an exemplary embodiment, the compound has a structure according to Formula (Il-b). In an exemplary embodiment, the compound has a structure according to Formula (Ill-b). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001. In an exemplary embodiment, the compound is Compound 1019. In an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.

[0134] In one aspect, the disclosure provides a method of preventing an infection in a patient, wherein the infection is with a bacterium, the method comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein. In an exemplary embodiment, the compound has a structure according to Formula (I-a). In an exemplary embodiment, the compound has a structure according to Formula (Il-a). In an exemplary embodiment, the compound has a structure according to Formula (Ill-a). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structure according to Formula (I-b). In an exemplary embodiment, the compound has a structure according to Formula (Il-b). In an exemplary embodiment, the compound has a structure according to Formula (Ill-b). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001.DB1 / 167011927.11In an exemplary embodiment, the compound is Compound 1019. Tn an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.

[0135] In one aspect, the disclosure provides a method of preventing a disease or disorder associated with infection with a bacterium in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein. In an exemplary embodiment, the compound has a structure according to Formula (I-a). In an exemplary embodiment, the compound has a structure according to Formula (Il-a). In an exemplary embodiment, the compound has a structure according to Formula (Ill-a). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structure according to Formula (I-b). In an exemplary embodiment, the compound has a structure according to Formula (Il-b). In an exemplary embodiment, the compound has a structure according to Formula (Ill-b). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001. In an exemplary embodiment, the compound is Compound 1019. In an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.

[0136] In some embodiments, the compound described herein is administered in the form of a pharmaceutically acceptable composition. In an exemplary embodiment, the pharmaceutically acceptable composition comprises at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

[0137] In some embodiments, the patient has an infection. In an exemplary embodiment, the patient has an infection in the oral cavity, genital tract, stomach, and / or colon.

[0138] In some embodiments, the bacterium is a gram-negative bacterium. In some embodiments, the bacterium is a gram-positive bacterium.

[0139] In some embodiments, the bacterium is an anaerobic bacterium. In some embodiments, the bacterium is an aerobic bacterium.DB1 / 167011927.11

[0140] In some embodiments, the bacterium is an antibiotic-resistant bacterium. Tn an exemplary embodiment, the antibiotic-resistant bacterium is resistant to a lincosamide such as clindamycin and / or lincomycin; a penicillin such as amoxicillin, ampicillin, carbenicillin, methicillin, piperacillin, and / or penicillin G; a cephalosporin such as cephalexin monohydrate, ceftriaxone, cefazolin, and / or cefuroxime; a sulfonamide; a fluoroquinolone such as ofloxacin, norfloxacin, ciprofloxacin, moxifloxacin, levofloxacin, delafloxacin, and / or gemifloxacin; a macrolide such as roxithromycin, clarithromycin, azithromycin, and / or erythromycin; a tetracycline; an aminoglycoside; and / or a carbapenem such as doripenem, ertapenem, imipenem, and / or meropenem.

[0141] In some embodiments, the bacterium is selected from an oral disease-associated bacterium, a bacterial vaginosis (BV)-associated bacterium, an endometriosis-associated bacterium, an oncogenic bacterium, a colorectal cancer (CRC)-associated bacterium, a gastric cancer-associated bacterium, a gastritis-associated bacterium, a Lyme disease-associated bacterium, an episodic fever-associated bacterium, a relapsing fever (RF)-associated bacterium, a gonorrhea-associated bacterium, and a syphilis-associated bacterium.

[0142] In some embodiments, the bacterium has a genus selected from Fusobacterium, Parvimonas, Peptoanaerobacter , Bacteroides, Clostridioides, Porphyromonas, Veillonella, Escherichia, Prevotella, Aggregatibacter, Gardnerella, Atopobium, Mobihincns, Peptostreptococcus, Clostridium, Helicobacter, Fannyhessea, Ureaplasma, Mycoplasma, Treponema, Borreliella, Borrelia, Brachyspira, Criibacterium, Leptospira, Moraxella, Parabacteroides, Sneathia, and Neisseria.

[0143] In an exemplary embodiment, the bacterium is a spirochete, or the bacterium has a genus selected from Fusobacterium and Clostridium. In an exemplary embodiment, the bacterium is a spirochete. In an exemplary embodiment, the bacterium has a genus selected from Fusobacterium and Clostridium.

[0144] In some embodiments, the bacterium is selected from Fusobacterium nucleatum, Fusobacterium periodonticum , Fusobacterium necrophorum, Porphyromonas gingivalis, Porphyromonas asaccharolytica, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Prevotella nigrescens, Veillonella parvula, Gardnerella vaginalis, Gardnerella leopoldii, Prevotella bivia, Prevotella corporis, Mobiluncus curtisii, Atopobium vaginae, DB1 / 167011927.11Criibacterium bergeronii, Ureaplasma urealyticum, Mycoplasma genital mm, Parvimonas micra, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, Bacteroides fragiHs, Clostridium septicum, Clostridium perfringens, Clostridium difficile, Clostridium tertium, Fusobacterium mortiferum, Peptoanaerobacter stomatis, Clostridioides difficile, Streptococcus gallolyticus, Helicobacter pylori, Treponema pallidum, Treponema denticola, Borreliella burgdorferi, Borreliella bavariensis, Borreliella garinii, Borrelia garinii, Borrelia spielmanii, Borrelia californiensis, Borrelia bissettiae, Borrelia burgdorferi, Borrelia genomospecies, Borrelia lanei, Borrelia sinica, Borrelia mayonii, Borrelia lusitaniae, Borrelia kurtenbachii, Borrelia andersonii, Borrelia coriaceae, Borrelia nietonii, Borrelia afzelii, Borrelia spielmanii, Borrelia hermsii, Borrelia turcica, Borrelia miyamotoi, Bacteroides ovatus, Brachyspira hyodysenteriae, Gardnerella vaginalis, Gardnerella leopoldii, Leptospira biflexa, Moraxella catarrhalis, Parabacteroides merdae, Sneathia amnii, and Neisseria gonorrhoeae.

[0145] In some embodiments, the bacterium has a genus selected from Staphylococcus, Streptococcus, and Enterococcus. In an exemplary embodiment, the bacterium is selected from Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dentisani, Streptoccocus mutans, Streptococcus salivarius, and Enterococcus faecalis.

[0146] In some embodiments, the bacterium is an oral disease-associated bacterium. In an exemplary embodiment, the oral disease-associated bacterium is selected from Fusobacterium nucleatum, Fusobacterium periodonticum, Fusobacterium varium, Fusobacterium necrophorum, Porphyromonas gingivalis, Porphyromonas asaccharolytica, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Prevotella nigrescens, and Veillonella parvula. In an exemplary embodiment, the oral disease-associated bacterium is selected from Fusobacterium nucleatum, Fusobacterium nucleatum subsp. animalis, Fusobacterium nucleatum subsp. polymorphum, Fusobacterium periodonticum, Fusobacterium necrophorum, Fusobacterium necrophorum ('Unde , Fusobacterium varium ClindaR, Porphyromonas gingivalis, Porphyromonas gingivalis HG66, Porphyromonas gingivalis 84-3, Porphyromonas asaccharolytica, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Prevotella nigrescens, and Veillonella parvula.

[0147] In some embodiments, the bacterium is a bacterial vaginosis (BV)-associated bacterium or an endometriosis-associated bacterium. In an exemplary embodiment, the bacterium is a BV-DB1 / 167011927.11associated bacterium or an endometriosis-associated bacterium selected from Gardnerella vaginalis Gardnerella leopoldii, Prevotella bivia, Prevotella corporis, Streptococcus agalactiae, Mobiluncus curtisii, Atopobium vaginae, Criibacterium bergeronii, Fusobacterium nucleatum, Ureaplasma urealyticum, and Mycoplasma genitalium .

[0148] In some embodiments, the bacterium is a colorectal cancer (CRC)-associated bacterium. In an exemplary embodiment, the CRC-associated bacterium is selected from Fusobacterium nucleatum, Parvimonas micra, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, Bacteroides fragilis, Clostridium septicum, Clostridium perfringens, Clostridium difficile, Fusobacterium mortiferum, Fusobacterium necrophorum, Peptoanaerobacter stomatis, Enterococcus faecalis, Enterococcus faecalis, Clostridioides difficile, Porphyromonas gingivalis, Porphyromonas asaccharolytica, Streptococcus gallolyticus, Veillonella parvula, Escherichia coli, and Staphylococcus aureus. In an exemplary embodiment, the CRC-associated bacterium is selected from Fusobacterium nucleatum, Fusobacterium nucleatum subsp. animalis, Parvimonas micra DSM2046, Parvimonas micra ATCC 23195, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, Bacteroides fragilis (ETBF), Clostridium septicum, Clostridium perfringens, Clostridium difficile, Fusobacterium nucleatum ATCC 25586, Fusobacterium nucleatum subsp. animalis ATCC 51191, Fusobacterium nucleatum subsp. vincentii ATCC 49256, Fusobacterium nucleatum subsp . polymorphum ATCC 10953, Fusobacterium mortiferum ATCC 25557, Fusobacterium necrophorum ATCC 25286, Parvimonas micra DSM20468, Peptoanaerobacter stomatis DSM28705, Enterococcus faecalis, Vancomycin- resistant Enterococcus faecalis (VRE), Enterotoxigenic Bacteroides fragilis, Clostridioides difficile ATCC 9689, Porphyromonas gingivalis ATCC 33277, Porphyromonas gingivalis ATCC BAA-308, Porphyromonas asaccharolytica ATCC 25260, Porphyromonas asaccharolytica ATCC 27908, Streptococcus gallolyticus, Veillonella parvula ATCC 10790, Escherichia coli MG1655, and Staphylococcus aureus HG003.

[0149] In some embodiments, the bacterium is a gastric cancer-associated bacterium or a gastritis-associated bacterium. In an exemplary embodiment, the bacterium is a gastric cancer- associated bacterium or a gastritis-associated bacterium, wherein the gastric cancer-associated bacterium and / or the gastritis-associated bacterium is Helicobacter pylori. In an exemplary embodiment, the bacterium is a gastric cancer-associated bacterium or a gastritis-associatedDB1 / 167011927.11bacterium selected from Helicobacter pylori ATCC700392, Helicobacter pylori ATCC43504, Helicobacter pylori ATCC700684, and Helicobacter pylori SSI.

[0150] In some embodiments, the bacterium is a syphilis-associated bacterium. In an exemplary embodiment, the bacterium is a syphilis-associated bacterium, wherein the syphilis- associated bacterium is Treponema pallidum.

[0151] In some embodiments, the bacterium is a Lyme disease-associated bacterium. In an exemplary embodiment, the bacterium is a Lyme disease-associated bacterium selected from Borreliella burgdorferi, Borreliella bavariensis, and Borreliella garinii. In an exemplary embodiment, the Lyme disease-associated bacterium is selected from Borreliella burgdorferi B31, Borreliella burgdorferi N40, Borreliella bavariensis, and Borreliella garinii .

[0152] In some embodiments, the bacterium is an episodic fever-associated bacterium or a relapsing fever (RF)-associated bacterium. In an exemplary embodiment, the bacterium is an episodic fever-associated bacterium or a RF-associated bacterium selected from Borrelia garinii, Borrelia spielmanii, Borrelia californiensis, Borrelia bissettiae, Borrelia burgdorferi, Borrelia genomospecies, Borrelia lanei, Borrelia sinica, Borrelia mayonii, Borrelia lusitaniae, Borrelia kurtenbachii, Borrelia andersonii, Borrelia coriaceae, Borrelia nietonii, Borrelia afzelii, Borrelia spielmanii, Borrelia hermsii, and Borrelia miyamotoi. In an exemplary embodiment, the episodic fever-associated bacterium or the RF-associated bacterium is selected from Borrelia garinii subsp. garinii DSM 10534, Borrelia spielmanii DSM 16813, Borrelia californiensis DSM 17989, Borrelia bissettiae DSM 17990, Borrelia burgdorferi DSM 4681, Borrelia genomospecies DSM 17991, Borrelia lanei DSM 17992, Borrelia sinica DSM 23262, Borrelia mayonii DSM 102811, Borrelia lusitaniae DSM 107168, Borrelia kurtenbachii ATCC BAA- 2495, Borrelia andersonii ATCC 700555, Borrelia coriaceae ATCC 43381, Borrelia nietonii TSD-355, Borrelia afzelii ATCC 51992, Borrelia spielmanii DSM 16813, Borrelia hermsii HS1, Borrelia hermsii DAH, and Borrelia miyamotoi ATCC BAA-3151.

[0153] In some embodiments, the bacterium is a gonorrhea-associated bacterium. In an exemplary embodiment, the bacterium is a gonorrhea-associated bacterium, wherein the gonorrhea-associated bacterium is Neisseria gonorrhoea . In an exemplary embodiment, the gonorrhea-associated bacterium is selected from Neisseria gonorrhoeae FA1090 and Neisseria gonorrhoeae MS 11.DB1 / 167011927.11

[0154] In some embodiments, the bacterium is Fusobacterium nucleatum. In some embodiments, the bacterium is Porphyronionas gingivalis. In an exemplary embodiment, the treatment treats or prevents cardiovascular disease. In an exemplary embodiment, the cardiovascular disease is heart failure.

[0155] In one aspect, the disclosure provides a method of treating a disease or disorder selected from acute bacterial sinusitis, acute otitis media, an anaerobic infection, bacteremia, bacterial vaginosis, cancer, cellulitis, chorioamnionitis, colitis, COPD exacerbations, dental caries, diarrhea, endocarditis, endometriosis, episodic fever, food poisoning, gas gangrene, gonorrhea, hemolytic uremic syndrome, impetigo, intra-abdominal abscess, intra-abdominal infections, Lemierre’s syndrome, Lyme disease, Lyme neuroborreliosis, maternal peripartum infections, meningitis, myonecrosis, neonatal early-onset sepsis, nongonococcal urethritis, odontogenic infections, opportunistic infections, osteomyelitis, pelvic inflammatory disease, peptic ulcer disease, peptoanaerobacter stomatis, periodontitis, peritonitis, pneumonia , purulent pericarditis, relapsing fever, sepsis, soft tick relapsing fever, syphilis, toxic shock syndrome, and urinary tract infection, the method comprising administering to a subject a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein. In an exemplary embodiment, the compound has a structure according to Formula (La). In an exemplary embodiment, the compound has a structure according to Formula (ILa). In an exemplary embodiment, the compound has a structure according to Formula (IILa). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structure according to Formula (Lb). In an exemplary embodiment, the compound has a structure according to Formula (ILb). In an exemplary embodiment, the compound has a structure according to Formula (IILb). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001. In an exemplary embodiment, the compound is Compound 1019. In an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.DB1 / 167011927.11

[0156] In some embodiments, the disease or disorder is a cancer is selected from colorectal cancer, gastric cancer, and gastric MALT lymphoma. In some embodiments, the disease or disorder is colorectal cancer.

[0157] In some embodiments, the disease or disorder is a cancer, wherein the subject is resistant or refractory to chemotherapy, radiotherapy, and / or immunotherapy.

[0158] In some embodiments, the disease or disorder is periodontal disease. In an exemplary embodiment, the disease or disorder is periodontitis.

[0159] In some embodiments, the disease or disorder is Lyme disease. In an exemplary embodiment, the disease or disorder is neuroborreliosis.

[0160] In some embodiments, the disease or disorder is a peptic ulcer.

[0161] In some embodiments, the disease or disorder is bacterial vaginosis.

[0162] In some embodiments, the disease or disorder is endometriosis.

[0163] In some embodiments, the disease or disorder is a urinary tract infection.

[0164] In one aspect, the disclosure provides a method of increasing efficacy of chemotherapy, radiotherapy, and / or immunotherapy treatment, comprising administering to a subject a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein. In an exemplary embodiment, the compound has a structure according to Formula (La). In an exemplary embodiment, the compound has a structure according to Formula (ILa). In an exemplary embodiment, the compound has a structure according to Formula (IILa). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structure according to Formula (Lb). In an exemplary embodiment, the compound has a structure according to Formula (ILb). In an exemplary embodiment, the compound has a structure according to Formula (IILb). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001. In an exemplary embodiment, the compound is Compound 1019. In an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.DB1 / 167011927.11

[0165] In one aspect, the disclosure provides a method of preventing plaque buildup or atherosclerosis, comprising administering to a subject a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein. In an exemplary embodiment, the compound has a structure according to Formula (I-a). In an exemplary embodiment, the compound has a structure according to Formula (Il-a). In an exemplary embodiment, the compound has a structure according to Formula (Ill-a). In an exemplary embodiment, the compound has a structure according to Formula (IV-a). In an exemplary embodiment, the compound has a structure according to Formula (I-b). In an exemplary embodiment, the compound has a structure according to Formula (Il-b). In an exemplary embodiment, the compound has a structure according to Formula (Ill-b). In an exemplary embodiment, the compound has a structure according to Formula (IV-b). In an exemplary embodiment, the compound is Compound 1001. In an exemplary embodiment, the compound is Compound 1019. In an exemplary embodiment, the compound is selected from Compounds 101-136. In an exemplary embodiment, the compound is selected from Compounds 1002-1018 and 1020-1036.

[0166] In an exemplary embodiment, the subject has a Porphyromonas gingivalis infection.

[0167] In some embodiments, the treatment has no or substantially no effect on gut microbiome. In some embodiments, “no or substantially no effect on gut microbiome” refers to reducing or not causing dysbiosis. In an exemplary embodiment, the treatment does not cause dysbiosis.

[0168] In some embodiments, the treatment has no or substantially no inhibition effect on gut commensal bacteria. In an exemplary embodiment, the gut commensal bacteria have a genus comprising Bifidobacterium, Lactobacillus, Blautia, and / or Roseburia. In an exemplary embodiment, the gut commensal bacteria comprise Bifidobacterium longum, Bifidobacterium bifidum, Bifobacterium animalis, Bifobacterium denlium, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus iners, Ligilactobacillus salivarius, Blautia producta, Akkermansia muciniphila, and / or Roseburia hominis.

[0169] In some embodiments, “no or substantially no inhibition effect on gut commensal bacteria” refers to a minimum inhibitory concentration (MIC) of the compound described herein which is lower for a bacterium than a gut commensal bacterium. In some embodiments, the MIC DB1 / 167011927.11of a gut commensal bacterium is greater than or equal to about 1 pg / ml of the compound described herein, greater than or equal to about 2 pg / ml of the compound described herein, greater than or equal to about 3 pg / ml of the compound described herein, greater than or equal to about 4 pg / ml of the compound described herein, greater than or equal to about 5 pg / ml of the compound described herein, greater than or equal to about 6 pg / ml of the compound described herein, greater than or equal to about 7pg / ml of the compound described herein, greater than or equal to about 8 pg / ml of the compound described herein, greater than or equal to about 9 pg / ml of the compound described herein, greater than or equal to about 10 pg / ml of the compound described herein, greater than or equal to about 11 pg / ml of the compound described herein, greater than or equal to about 12 pg / ml of the compound described herein, greater than or equal to about 13 pg / ml of the compound described herein, greater than or equal to about 14 pg / ml of the compound described herein, greater than or equal to about 15 pg / ml of the compound described herein, greater than or equal to about 16 pg / ml of the compound described herein, greater than or equal to about 17 pg / ml of the compound described herein, greater than or equal to about 18 pg / ml of the compound described herein, greater than or equal to about 19 pg / ml of the compound described herein, greater than or equal to about 20 pg / ml of the compound described herein, greater than or equal to about 25 pg / ml of the compound described herein, greater than or equal to about 30 pg / ml of the compound described herein, greater than or equal to about 32 pg / ml of the compound described herein, greater than or equal to about 35 pg / ml of the compound described herein, greater than or equal to about 40 pg / ml of the compound described herein, greater than or equal to about 45 pg / ml of the compound described herein, greater than or equal to about 50 pg / ml of the compound described herein, greater than or equal to about 55 pg / ml of the compound described herein, greater than or equal to about 60 pg / ml of the compound described herein, greater than or equal to about 64 pg / ml of the compound described herein, or greater than or equal to about 65 pg / ml of the compound described herein.

[0170] In some embodiments, the treatment preserves the symbiotic microbiome of the oral, gastrointestinal, and / or vaginal environments.

[0171] In some embodiments, the treatment selectively targets pathogenic microorganisms while maintaining the integrity of the symbiotic microbiome in the oral, gut, and / or vaginal ecosystems.DB1 / 167011927.11

[0172] In some embodiments, the treatment reduces disruption of gut commensal bacteria relative to treatment with a broad spectrum antibiotic.

[0173] In some embodiments, the treatment reduces or delays the emergence of antibiotic resistance relative to treatment with a broad spectrum antibiotic.

[0174] The disclosure is further illustrated by the Examples that follow. The Examples are not intended to define or limit the scope of the invention.EXAMPLESExample 1: Synthetic methods

[0175] The compounds of the disclosure may be prepared using the techniques described below. Some of the schemes and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in a number of treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974 et seq.). Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO2 from the decarboxylation of a diacid, etc f In addition, in some instances, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0176] Starting materials and reagents may be obtained from commercial sources or may be synthesized in analogy to or according to methods that are known in the art. In the preparation of starting materials, existing functional groups which do not participate in the reaction should, if necessary, be protected. Protecting groups, their introduction and their removal are described herein.

[0177] In some of the reaction schemes and examples described herein, certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modifyDB1 / 167011927.11physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0178] Generally, the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e g., -78° C. to 0° C ). Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., whether or not expressly using the word “range,” also includes the indicated endpoints.

[0179] Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-l-ol, propan-2-ol, butan-l-ol, 2-methyl-propan-l-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan- l-ol, 3- methyl-butan-l-ol, hexan-l-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2- methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e g., diethyl ether, di-isopropyl ether, dibutyl ether, 1,2-dimethoxy ethane, 1,2-di ethoxy -ethane, 1 -methoxy-2-(2-methoxy-ethoxy)-ethane, 1 -ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-di oxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl- pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide,DB1 / 167011927.11dimethyl sulfoxide, tetrahydro-thiophene-1,1, -dioxide); and phosphorus-containing solvents (e g., hexamethylphosphoric triamide).

[0180] General Procedure 1 shows exemplary methods for preparing compounds of Formula (I-a), Formula (Il-a), Formula (Ill-a), Formula (IV-a), Formula (I-b), Formula (Il-b), Formula (Ill-b), and Formula (IV-b), such as Compounds 101-136 and Compounds 1001-1036, wherein the substituents are as defined for Formula (I-a), except where further noted. The following general procedures outline a key transformation used in the synthesis of the compounds disclosed herein by reacting a carboxyl group with an amine, following standard literature- reported conditions. While these general procedures provide exemplary foundational methodology, variations in reagents, stoichiometry, reaction time, and temperature may apply depending on the specific compound, with detailed conditions reported alongside each individual example, as would be understood by one of ordinary skill in the art.General Procedure I. Exemplary reaction of intermediate A with intermediate B to afford compounds of Formula (I-a), Formula (Il-a), Formula (Ill-a), Formula (IV-a), Formula (I-b), Formula (Il-b), Formula (Ill-b), and Formula (IV-b) of the instant disclosure

[0181] Intermediates A and B of General Procedure 1 are readily accessible using established literature protocols and commercially available building blocks to prepare compounds of Formula (I-a), Formula (Il-a), Formula (Ill-a), Formula (IV-a), Formula (I-b), Formula (Il-b), Formula (Ill-b), and Formula (IV-b), such as Compounds 101-136 and Compounds 1001-1036.

[0182] General Procedure 2 shows exemplary methods for preparing compounds of Formula (I-b), Formula (Il-b), Formula (Ill-b), and Formula (IV-b), such as Compounds 102-118, Compounds 120-136, Compounds 1002-1018, and Compounds 1020-1036, wherein the substituents are as defined for Formula (I-b), except where further noted. The following general procedures outline a key transformation used in the synthesis of the compounds disclosed herein by reacting a hydroxyl group with a moiety (X) (e.g. a halide) of a precursor of R1(X-R1),DB1 / 167011927.11following standard literature-reported conditions. While these general procedures provide exemplary foundational methodology, variations in reagents, stoichiometry, reaction time, and temperature may apply depending on the specific compound, with detailed conditions reported alongside each individual example, as would be understood by one of ordinary skill in the art.General Procedure 2.Compound A Compound B

[0183] X-R1is readily accessible using established literature protocols and commercially available building blocks to prepare compounds of Formula (I-b), Formula (Il-b), Formula (III- b), and Formula (IV-b), such as Compounds 102-118, Compounds 120-136, Compounds 1002- 1018, and Compounds 1020-1036.

[0184] General methods for synthesizing ADC238, ADC238-1, and prodrugs thereof is also found in, for example, Yang et al. "Design, Synthesis, and Biological Evaluation of 1, 3, 4- Thiadiazole Derivatives as Novel Potent Peptide Deformylase Inhibitors for Combating Drug- Resistant Gram-Positive and-Negative Bacteria." Journal of Medicinal Chemistry 68, no. 3 (2025): 2942-2962, which is incorporated herein by reference in its entirety.

[0185] Scheme 1 shows an exemplary synthetic scheme for preparing ADC238 and ADC238- 1.DB1 / 167011927.11Scheme 1. Synthetic scheme for preparing ADC 238 and ADC238-1

[0186] Exemplary prodrugs of ADC238 and ADC238-1 are shown below.DB1 / 167011927.11DB1 / 167011927.11

[0187] Synthetic schemes for preparing exemplary prodrugs of ADC238, Compounds 1002 (“Prodrug- 1”), 1003 (“Prodrug-2”), 1004 (“Prodrug-3”), and 1005 (“Prodrug-4”), are shown in Figure 3. Other prodrugs of ADC238 and ADC238-1, such Compounds 1006-1018 and 1020- 1036, are readily prepared using established literature protocols and commercially available building blocks to prepare these compounds.

[0188] While these general procedures provide exemplary foundational methodology, variations in reagents, stoichiometry, reaction time, and temperature may apply depending on the specific compound, with detailed conditions reported alongside each individual example, as would be understood by one of ordinary skill in the art.DB1 / 167011927.11Example 2: Minimal inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) protocols

[0189] The following protocols for MIC and MBC are by CLSI guidelines M07 (Edl2, 2024); Ml 1 (9th ed. / latest 2025); M45 (3rd ed., 2016); M07 with modifications; M100 (Ed36, Jan 2026) (each of which are incorporated herein by reference in its entirety). The protocols describe the methods used to obtain the data described in Examples 2-5.(1) Fusobacterium spy. and Poryhyromonas syy. (Oral & CRC-associated)

[0190] Exemplary species: Fusobacteriiim nucleatum, Fusobacteriiim periodonticum , Porphyromonas gingival 'is, Porphyromonas asaccharolytica.

[0191] Biosafety note BSL1 / 2: Strict anaerobes, handle in an anaerobic chamber

[0192] MIC protocol (broth microdilution). Medium: Wilkins-Chalgren Anaerobe Broth (Oxoid) or Brain Heart Infusion (BHI) supplemented with 5 pg / mL hemin, 1 pg / mL vitamin Ki, and 0.5% yeast extract. Inoculum prep: Grow bacteria anaerobically at 37°C for 24-48 h. Adjust overnight culture to 0.5 McFarland (~1 x 108CFU / mL). Dilute 1 : 100 in fresh anaerobe broth to achieve final inoculum ~10fiCFU / mL. Assay: Dispense 100 pL of medium into 96-well anaerobic plates. Serially dilute Formibactin A (2* dilutions across wells). Add equal volume (100 pL) bacterial suspension to reach final inoculum ~5 / 105CFU / mL. Incubate anaerobically 37°C, 48 h (avoid shaking). MIC: The lowest concentration with no visible turbidity.Optionally confirm with ODsoo measurement post-incubation.

[0193] MBC protocol From wells showing no visible growth, spot 10 pL onto anaerobic BHI-HK agar plates (with hemin and vitamin Ki). Incubate anaerobically for 48-72 h. MBC = lowest concentration producing >99.9% kill (>3-log CFU reduction vs initial inoculum).(2) Prevotella, Aggregatibacte and Veillonella

[0194] Exemplary species: Prevotella intermedia, Prevotella nigrescens, Aggregatibacter actinomycetemcomitans, Veillonella parvula.

[0195] MIC protocol (broth microdilution). Medium: Supplemented BHI broth (hemin + vitamin Ki + 5% lysed horse blood (ox Prevotella and Veillonella). F or Aggregatibacter (facultative anaerobe), use cation-adjusted Mueller-Hinton broth (CAMHB) + 5% lysed horseDB1 / 167011927.11blood and 20 pg / mL [3-NAD. Inoculum: 0.5 McFarland suspension (1 *108CFU / mL), diluted 1 : 100 into broth. Assay conditions: Anaerobic for Prevotella and Veillonella; 5% CO2 for Aggregatibacter. 96-well plate, 200 pL total volume. Incubate 37°C for 48 h (Prevotella) or 24 h (Aggregatibacter). Readout: No turbidity — MIC.

[0196] MBC protocol. From wells showing no visible growth, spot 10 pL onto anaerobic BHI-HK agar plates (with hemin and vitamin Ki). Incubate anaerobically for 48-72 h. MBC = lowest concentration producing >99.9% kill (>3-log CFU reduction vs initial inoculum).(3) Gardnerella, Atopobium, Mobiluncus, and related vaginal anaerobes

[0197] MIC protocol (broth microdilution). Medium: NYC broth or supplemented BHI with 5% horse serum, 0.25% glucose, 1% yeast extract, and 5 pg / mL hemin. pH ~6.8-7.0 is ideal. Inoculum: Grow 24 h anaerobically, adjust to 0.5 McFarland, dilute to 106CFU / mL final in wells. Assay: Formibactin A 2-fold serial dilutions (typically 0.008-128 pg / mL). Anaerobic incubation 37°C for 48 h. Reading: MIC = lowest concentration showing no visible turbidity or redox shift (Resazurin can be added at 0.01% to visualize growth endpoints).

[0198] MBC protocol. Plate 10 pL of clear well suspensions onto Modified Columbia Blood Agar for 48 h anaerobic incubation. Calculate MBC (99.9% kill).(4) Peptostreptococcus, Parvimonas, and Clostridium spp. (CRC-associated)

[0199] Biosafety note BSL1 / 2: Strict anaerobes, handle in an anaerobic chamber.

[0200] Medium: Wilkins-Chalgren or Reinforced Clostridial Medium (RCM). Conditions: 37°C, 48 h anaerobic. Inoculum: 5 x 105CFU / mL final.

[0201] MIC / MBC protocols Measured exactly as with Fusobacterium, noting that sporulation (in Clostridium) requires fully reduced media. Check viability by plating on anaerobic blood agar. For Clostridium difficile, supplement medium with 0.05% L-cysteine and pre-reduce 24 h before use. Use stationary-phase vegetative cells, not spores.(5) Helicobacter pylori (gastric isolates)

[0202] Exemplary strains: ATCC700392, ATCC43504 (MTZR), ATCC700684 (CLRR), SSI.

[0203] Microaerophilic bacterium.DB1 / 167011927.11

[0204] MIC protocol (per CLSI M07-A11 modifications for Helicobacter pylori). Medium: Brucella broth + 5% fetal bovine serum (or horse serum). Inoculum prep: Grow 48 h on Brucella agar with 5% defibrinated sheep blood under microaerophilic conditions (5% O2, 10% CO2, 85% N2). Suspend colonies in broth to 2.0 McFarland («1 * 108CFU / mL). Dilute to 1 x 106CFU / mL final inoculum. Assay: Prepare 2-fold serial dilutions of Formibactin A in 96-well microplates. Add bacterial inoculum (100 pL / well; final volume 200 pL). Incubate 37°C, microaerophilic, 72 h (without shaking). MIC reading: Lowest well without visible growth (can confirm using ODeoo or resazurin viability staining).

[0205] MBC protocol. From MIC plate, inoculate 10 pL of non-turbid wells onto Brucella blood agar (5% sheep blood). Incubate microaerophilically 72-96 h. MBC = concentration yielding >99.9% CFU reduction.6) Mycoplasma and Ureaplasma species

[0206] Minimal media and colorimetric detection MIC protocol. Medium: SP-4 broth (for Mycoplasma genitalium) or 10B broth (for Ureaplasma urealyticum) with phenol red as pH indicator. Inoculum: 104- 105CFU / mL in broth. Assay: 96-well format, serial 2* dilutions of Formibactin A. Incubate 37°C, ambient atmosphere up to 5 days. Reading: MIC = lowest concentration without color change (red yellow due to pH shift).

[0207] MBC protocol Subculture from each non-color-changed well onto solid SP-4 or A7 agar; incubate 5-7 days. MBC: lowest concentration producing >99.9% CFU reduction.(7) Borrelia species

[0208] MIC protocol (e.g. Borrelia burgdorferi). Procol follows CLSI M45 guidelines for fastidious bacteria, adapted from M07 broth microdilution methods using Barb our- Stoenner- Kelly (BSK) medium without specific approved breakpoints. Key materials include BSK-II or BSK-H medium (pH ~7.6) supplemented with phenol red (25 mg / L) for optional colorimetric reads, sterile 96-well microtiter plates, antibiotic stock for Formibactin A was prepared in log2 dilutions, low-passage B. burgdorferi inoculum standardized to 105-106 cells / mL via dark-field microscopy or Petroff-Hausser counting, growth / sterility controls, and QC strains such as S. aureus ATCC 29213, plus equipment like a 33 °C microaerophilic incubator (5% CO2), plate reader (562 / 630 nm), and dark-field scope. In the procedure, dispense 100 pL antibioticDB1 / 167011927.11dilutions into plates, add 100 pL inoculum suspension (final ~5* 10A5 CFU / mL), seal to prevent evaporation, and incubate for 72 hours at 33°C with 5% CO2; read MIC endpoints visually (no pellicle / sediment), microscopically (no motile spirochetes in 5-10 fields), or calorimetrically (absorbance reduction <10% from T=0), running tests in triplicate to derive MIC50 / 90 values.

[0209] MBC determination: Subculture 10 pL from clear wells into 750 pL drug-free BSK, reincubate 14-21 days and confirm no growth microscopically.(8) Neisseria gonorrhoeae

[0210] MIC protocol The protocol for Neisseria gonorrhoeae follows CLSI Ml 00 (broth microdilution or agar dilution) and M45 guidelines for fastidious bacteria, using cation-adjusted Mueller-Hinton broth (CAMHB) supplemented with 5% lysed horse blood or 1% hemoglobin, pH 7.2-7.4, in 96-well plates at 35±2°C in 5% CO2 for 20-24 hours. Prepare twofold serial dilutions of antibiotics (e.g., ceftriaxone, Formibactin A) from 0.008-128 pg / mL in 50 pL volumes per well, add 50 pL standardized inoculum (0.5 McFarland ~l-2><105 CFU / mL, direct colony suspension), include growth (no drug), sterility (no inoculum), and QC strains like N. gonorrhoeae ATCC 49226 (MIC range for ceftriaxone 0.008-0.06 pg / mL), then read MIC as the lowest concentration preventing >80% growth reduction by unaided eye or 50% by spectrophotometer at 600 nm.Example 3: Antibiotics for diseases caused b Spirochetes and Fusobacterium species

[0211] Peptide deformylase (PDF) is a critical enzyme in bacteria that catalyzes the removal of the formyl group from the N-terminal methionine of newly synthesized polypeptides. This step is essential for proper protein maturation and function in bacteria. PDF remains an attractive target for antibiotic development due to its essential role in bacterial physiology, conservation across bacterial species, and absence in humans. The PDF inhibitor class of antibiotics has been used against different pathogens, which can potentially lead to the pathogens developing spontaneous antibiotic resistance.

[0212] PDF is highly conserved across a wide range of bacterial species but species-specific variations in PDF structure and function provide opportunities for designing both broadspectrum and narrow- spectrum antibiotics. By leveraging these differences, a narrow spectrum PDF inhibitor ADC238 (also referred to as BB-83698) and analogue ADC238-1 againstDB1 / 167011927.11Spirochetes and Fusobacterium species were developed. BB-83698 IV (ADC238) and BB- 81384 oral (ADC238-1) was developed by British Biotech in collaboration with Genesoft entered Phase I studies in humans in October 2002. These drugs were discontinued after Phase I trials due to limited activity against only pneumococci. Interestingly, no toxic side effects were reported for these compounds in human trials.ADC 238-1

[0213] We examined the spectrum of activity of ADC238 in detail and found that it is active against spirochetes. ADC238 has the highest activity against Treponema pallidum, the causative agent of syphilis, with a minimal inhibitory concentration (MIC) of 0.1 pg / ml. ADC238 is evenly active against B. burgdorferi (MIC of 1 pg / ml) and other species responsible for Lyme disease B. garinii and B. bavariensis (Table 1). We tested ADC238 in a mouse model of acute Lyme disease. BB-83698 is reasonably well-absorbed by the oral route, with a mean bioavailability of 50 % in mice (80 mg / kg / day). We tested oral administration of ADC238 (80 mg / kg / day). After 2 days of treatment, ADC238 cleared the infection. There were no indications of toxicity even at very high doses, suggesting the ADC238 is oral dosage safe and effective (Figure 1). ADC238-1 (previously BB-81384) was developed as an analogue of ADC238 (previously BB-83698) with high oral bioavailability (88% oral bioavailability at 50 mg / kg / day). We were unable to obtain spontaneous mutants of Borreliella burgdorferi B31 resistant to ADC238 even when plating on media with a low dose (4 x MIC) of ADC238.DBl / 167011927.11

[0214] ADC238 is very potent against disease-initiating bacteria oral microbes, sparing healthpromoting microflora like lactobacilli. ADC238 is very effective in killing Fusobacterium species and Porphyromonas gingivalis which are causative agent for Periodontitis and (Table 1). F. nucleatum produced resistant mutants with a frequency of 2* 109at 4x MIC of ADC238 (~ 0.1 pg / ml). We then tested higher concentrations of ADC238 (from 16 xMIC ~ 0.4 pg / ml up to 100*MIC~ 2.5 pg / ml) and could not get spontaneous resistant mutants.

[0215] ADC238 is relatively ineffective against both Gram-positive and Gram-negative gut symbionts tested so far (Table 1). ADC238 lacks activity against Enter obacteriaceae, non- fermentative gram-negative bacilli and non-spore forming fermentative gram-positive bacilli. Table 1. Minimum inhibitory concentration (MIC) of ADC 238 and clinically relevant antibiotics against spirochaetes, human pathogens and commensals.

[0216] In summary, the PDF inhibitors described herein (e. , ADC238 and analogs thereof) are potent against spirochetes, fusobacterium species, and clostridia species. ADC238 and analog demonstrated activity against spirochetes and fusobacterium species in vitro with no spontaneous resistance, and ADC238 showed excellent in vivo efficacy in the mouse borrelia infection model. ADC238 and analogs are narrow-spectrum antibiotics that do not disturb the DBl / 167011927.11gut microbiome. The good oral bioavailability and no toxicity make ADC238 and ADC238-1 ideal choices as antibiotics for treatment (e.g., treating infections caused by spirochetes, fusobacterium species, and / or clostridia species).Example 4: Antibiotic against colorectal cancer (CRC)-associated pathogens

[0217] Colorectal cancer (CRC) is a major cause of cancer mortality, with incidence rising globally. Alongside genetic mutations driving tumorigenesis, several gut bacteria, including Fusobacterium nucleatum, Parvimonas micra. and Bacteroides fragilis, promote cancer through inflammation and disruption of epithelial barriers. Conventional broad-spectrum antibiotics can reduce these pathogens but often harm beneficial microbiota, leading to complications such as dysbiosis, impaired immunity, and reduced treatment efficacy.[00218J Selective antimicrobial strategies are needed to specifically target tumor-promoting bacteria while preserving the protective microbiome. Disclosed herein is the use of Formibactin A (ADC238), a peptide deformylase inhibitor, as a potent and selective antibiotic against pathogenic strains without exhibiting cytotoxicity to mammalian cells.ADC238

[0219] ADC238 demonstrated excellent activity against F. nucleatum and other clinically relevant Fusobacterium species such as F. polymorphum and F. animalis, with MICs of 0.004 to 0.25 pg / ml.ADC238 showed activity against other CRC -associated pathogens such as enterotoxigenic B. fragilis, E. faecalis, P. micra, and Peptoanaerobacter stomatis (Table 2). ADC238 is bactericidal against most of CRC pathogens without affecting beneficial microbes such as Lactobacilli, Akkermansia, Roserburia and Bifidobacteria.Table 2. Minimum inhibitory concentrations (MIC) and cytotoxicity of ADC 238 and clindamycin.DBl / 167011927.11

[0220] To assess the ex vivo efficacy of the compounds against pathogens associated with colorectal cancer (CRC), a 3D bacteria- spheroid co-culture (BSCC) model was employed. This system effectively models key features of the tumor microenvironment, such as oxygen and nutrient gradients, cellular metabolism, and host microbe interactions, making it an attractive model for studying intra-tumor anaerobic bacteria. F. nucleatum, a CRC-associated bacterium linked to poor clinical outcomes and resistance to therapy, served as the primary focus of the initial evaluation. 3D tumor spheroids containing F. nucleatum were generated (Figure 2A) and then treated with ADC238 at 10*MIC, which eliminated the bacterial burden (Figures 2B-2C).DBl / 167011927.11

[0221] Traditional broad-spectrum antibiotics destroy good commensal bacteria, which play important role in cancer therapy and treatment. The selective antibacterial activity of ADC238 against cancer-associated pathogens provides for an improved cancer therapy.Example 5: Formibactin A against human pathogens

[0222] There is a growing need to develop targeted antibiotics that can address oral disease- associated pathogens, bacterial vaginosis (BV)-associated / endometriosis-associated taxa, oncogenic bacteria like H. pylori, and colorectal cancer (CRC)-linked microbes, because many of these organisms belong to overlapping dysbiotic consortia (for example, Fusobacterium, Prevotella, Porphyromonas, H. pylori)' that colonize the oral cavity, genital tract, and colon and have been implicated in inflammation-driven carcinogenesis and ectopic endometrial implantation. Here we demonstrate Formibactin A, an antibiotic which spares beneficial commensals while suppressing keystone pathogens.Table 3. Oral Pathogens.DBl / 167011927.11Table 4. Colorectal cancer associated pathogens.DB1 / 167011927.11Table 5. Women health - Bacterial vaginosis and endometriosis associated pathogens.Table 6. Gastric cancer and gastritis related pathogens.Example 6: Formibactin A against Borrelia

[0223] Borrelia is a genus of bacteria of the spirochete phylum. Several species of which cause Lyme disease. Formibactin A kills Borrelia species with a MIC of 2 ug / ml or less.DB1 / 167011927.11Table 7. Borrelia SpeciesExample 7: Formibactin A against Neisseria gonorrhoeae

[0224] Neisseria gonorrhoeae, the Gram-negative diplococcus behind gonorrhea, is a major global health problem. It spreads easily, often without symptoms, and resists antibiotics fast. Left untreated, it causes pelvic inflammatory disease, infertility, epididymitis, disseminated infections, and higher HIV risk-making quick antibiotic treatment essential. Neisseria gonorrhoeae has developed resistance against sulfonamides, penicillin, tetracyclines, quinolones, and macrolides over time, so third-generation cephalosporins like ceftriaxone are now the main option per WHO and CDC guidelines. Leaning on one class raises alarms about cephalosporin- resistant superbugs, so we need new drugs, better selectivity. Here we demonstrate that compounds of the disclosure (e.g., Compound 1001; Formibactin A) kill Neisseria gonorrhoeae FA1090 and MSI 1 with MIC of 1 pg / ml. At the same time, Compound 1001 (Formibactin A) spares commensal lactobacilli in vaginal microbiome.DB1 / 167011927.11

[0225] Formibactin A against Neisseria gonorrhoeae is tested using the Neisseria gonorrhoeae GC panel, a culture collection of 50 Neisseria gonorrhoeae isolates.Example 8: Efficacy of ADC238

[0226] Using the mouse model established in Example 4, preliminary testing was performed using ADC238 (which showed promising results in ex vivo tumor spheroid model, as discussed above) to treat CRC. CT26 cells were inoculated bilaterally into Balb / c mice and then injected with F. micleatum 12230 as described above in Example 4 (n=6). The next day, 1 mg / ml ADC238 was injected into the tumors of 3 of the 6 mice. Ten days later, the tumor sizes were measured as below (Table 8). Antibiotic treatment group showed a trend of reduced tumor growth control.Table 8. Efficacy ofADC238 against CT26 cells containing Fusobacterium.

[0227] Next, the efficacy of ADC238 was assessed in a murine model of neuroborreliosis, in which B. burgdorferi colonizes the dura mater. Mice were infected intradermally with B. burgdorferi B31-A3, and spirochetes were allowed to disseminate seven days post-infection. Animals were then treated orally with ADC238 or doxycycline (100 mg / kg, twice daily) for five consecutive days. Consistent with prior observations, B. burgdorferi was not detected in the brain tissue of infected animals by culture, irrespective of treatment. In contrast, dura mater samples from untreated mice remained culture-positive up to 75 days post-infection. As expected, untreated controls yielded viable spirochetes, whereas no B. burgdorferi were recovered from the dura mater of mice treated with either ADC238 or doxycycline (Table 9).Table 9. Efficacy ofADC238 and doxycycline against murine neuroborreliosis.DBl / 167011927.11

[0228] Doxycycline is the standard prophylactic for adults to prevent Lyme disease after a tick bite. To test if ADC238 can be used as prophylaxis, single-dose efficacy was compared in a murine model of tick-transmitted B. burgdorferi infection. Groups of C3H mice received a single oral dose of ADC238 or doxycycline (each at 100 mg / kg) or vehicle control immediately following removal of Ixodes scapularis nymphs infected with B. burgdorferi . Three weeks later, tissue cultures revealed that ADC238 protected 50% of the mice from Borrelia infection, while doxycycline offered no protection in the same setup. Then, a double dose regimen was evaluated with C3H mice exposed to infected ticks (two oral doses of ADC238 or doxycycline, 100 mg / kg, at 0 and 24 h post-tick removal). ADC238 fully protected all animals from infection, as confirmed by sterile cultures, while doxycycline again failed to prevent borreliosis (Table 3). Table 10. The efficacy of ADC238 arid doxycycline as tick bite prophylaxis agents.

[0229] Figures 4A and 4B show the efficacy of ADC238 in a murine Lyme borreliosis model. Figure 4A shows the quantification of B. burgdorferi in tissues (ear and muscle) of animals. The amount of 16S rRNA was converted into cell count. Five mice per group were infected and given ADC238 or doxycycline orally; infected non-treated group (NT) was given drug-free vehicle for 5 days. C3H mice were infected subcutaneously with B. burgdorferi N40, and after 3DBl / 167011927.11weeks were treated for 5 days with ADC238 or doxycycline via oral gavage. All mice were treated twice a day, and the total daily dose (mg / kg) is indicated. After treatment, the presence of B. burgdorferi cells was detected by dark-field microscopy from culture of a whole ear in BSK-II media. The percentage of mice from which cultures were positive is reported in Figure 4B.Materials and Methods

[0230] Murine Lyme Borreliosis infection model: All animal experiments were approved by the Northeastern University Institutional Animal Care and Use Committee (IACUC; protocol number 16-0619). Wild type female C3H mice (Charles River Laboratories) were). Five-week- old female wild-type C3H / HeN mice (Charles River Laboratories) were infected subcutaneously in the flank with 105mid-log-phase B. burgdorferi N40 (clone DI 0E9) cells or intradermally in the ear pinnae with bioluminescent B. burgdorferi ML23 pBBE221uc (a lp25-deficient B31 derivative carrying codon-optimized luciferase under the flaB promoter; n > 3 mice per treatment group).[00231J Infection was allowed to establish for 2 weeks, confirmed by plating ear-punch biopsies (2 -mm diameter) onto semi-solid BSK-II medium supplemented with 1.5% gelatin; positive growth was observed in all animals within 14 days. For bioluminescence imaging, mice received intraperitoneal injection of 5 mg VivoGlo d-luciferin (Promega) dissolved in 100 pl. sterile PBS, followed 10 min later by whole-body imaging (2-5 min exposure) on an IVIS Spectrum in vivo imaging system (PerkinElmer) to quantify luminescence.

[0232] Treatment began immediately after infection confirmation: mice received twice-daily oral gavage for 5 consecutive days with vehicle; untreated controls), doxycycline (100 mg kg1body weight; positive treatment control), or Formibactin A (10, 25 or 50 mg kg1). Infection clearance was monitored by ear-punch biopsies collected every 12 h post-treatment initiation (plated in semi-solid gelatin / BSK-II medium) and by whole-ear cultures at necropsy on day 21 post-infection. Bacterial outgrowth was scored after 14-21 days of incubation (34 °C, microaerophilic).

[0233] Estimation of Borrelia burden in mouse tissues by quantitative PCR: The mouse and B. burgdorferi RNA from infected tissues were extracted using RNAeasy Mini KitDB1 / 167011927.11(QIAGEN). cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kits (Applied Biosysterms). Real-time PCR was performed with primers targeting the16S rDNA gene (F: 5'- GGT CAA GAC TGA CGC TGA GTC and R: 5 GGC TTA GAA CTA ACG CTG) using SYBR green Supermix (Bio-RAD). B. burgdorferi N40 copy number was normalized to cDNA standard curve synthesized from a known copy numberof B. burgdorferi cells.

[0234] Murine Neuroborreliosis model: All biohazard and animal experiments were carried out in accordance with approved protocols from the University of North Dakota Institutional Biosafety Committee (protocol number IBC2510-0054) and the Animal Care and Use Committee (IACUC protocol number 2501-0001; Animal Welfare assurance number A3917-01), respectively. Low passage B. burgdorferi strain B31 A3 cultured to mid-log phase in BSK-II medium at 37°C, 5% CO2, and quantified by dark field microscopy using a Petroff-Hausser chamber. C3HeB / FeJ (C3H; stock # 000658) were purchased from The Jackson Laboratory. 6- 8 week-old male and female mice were used. For infections by needle inoculation, animals were placed under anesthesia using isoflurane inhalation, followed by subdermal inoculation with 100 uL of BSK-II medium containing 106spirochetes. Infections were confirmed in mice by collecting ~80 pL blood from the saphenous vein at day 7 post-infection and cultured in BSK-II. Ear tissue was also isolated and cultured at times of sacrifice of all animals. Dark-field microscopy was used to confirm the presence of viable spirochetes for each cultured blood / tissue sample. Formibactin A and Doxycycline (Research Products International) at 2mg / dose were started on day 8, twice a day (every 12 hours) for 5 days. Drugs were administered via oral gavage (0.1 ImL per dose) to equal numbers of male and female animals. Mice were sacrificed after 5 days of drug treatment. Skullcaps with attached dura were isolated by craniotomy and dura mater removed from the skullcaps as previously described and cultured in BSK II media. Brains were sliced into two halves, with one half cultured in BSK II medium. / n vivo efficacy for tumor progression with Fusobacterium infection: CT26 cells were inoculated bilaterally into Balb / c mice and then injected with Fusobacterium nucleatum Fn 12230 (n=6). The next day, 1 mg / ml ADC238 was injected into the tumors of 3 of the 6 mice. Ten days later, the tumor sizes were measured. Antibiotic treatment group showed a trend of reduced tumor growth control.DB1 / 167011927.11Example 9: Formibactin A against bacteria.

[0235] Formibactin A was tested against the bacteria shown in Table 11.Table 11. Formibactin A against bacteria.DBl / 167011927.11

Claims

CLAIMS1. A method of treating a patient infected with a bacterium, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I-a):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted -C10 aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

2. A method of treating an infection in a patient, wherein the infection is with a bacterium, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I-a):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)x0C(0)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(0)(CH2)xC(0)Ra, -P(0)(0Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Cs-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cx-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached toform optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

3. A method of treating a disease or disorder associated with an infection with a bacterium in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I-a):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

4. The method of any one of claims 1 to 3, wherein the patient has an infection in the oral cavity, genital tract, stomach, and / or colon.

5. The method of any one of claims 1 to 4, wherein the bacterium is selected from an oral disease-associated bacterium, a bacterial vaginosis (BV)-associated bacterium, an endometriosis-associated bacterium, an oncogenic bacterium, a colorectal cancer (CRC)-associated bacterium, a gastric cancer-associated bacterium, a gastritis-associated bacterium, a Lyme disease-associated bacterium, an episodic fever-associated bacterium, a relapsing fever (RF)-associated bacterium, a gonorrhea-associated bacterium, and a syphilis-associated bacterium.

6. The method of any one of claims 1 to 5, wherein the bacterium has a genus selected from Fusobacterium, Parvimonas, Peptoanaerobacter, Bacteroides, Clostridioides, Porphyromonas, Veillonella, Escherichia, Prevotella, Aggregatibacter, Gardnerella, Atopobium, Mobiluncus, Peptostreptococcus, Clostridium, Helicobacter, Fannyhessea, Ureaplasma, Mycoplasma, Treponema, Borreliella, Borrelia, Brachyspira, Criibacterium, Leptospira, Moraxella, Parabacteroides, Sneathia, and Neisseria.

7. The method of any one of claims 1 to 6, wherein the bacterium is a spirochete, or the bacterium has a genus selected from Fusobacterium and Clostridium.

8. The method of any one of claims 1 to 7, wherein the bacterium is selected from Fusobacterium nucleatum, Fusobacterium periodonticum, Fusobacterium necrophorum, Porphyromonas gingivalis, Porphyromonas a ciccharolytica. Aggregatibacter actinomycetemcomitans, Prevotella intermedia Prevotella nigrescens, Veillonella parvula, Gardnerella vaginalis, Gardnerella leopoldii, Prevotella bivia, Prevotella corporis, Mobiluncus curtisii, Atopobium vaginae, Criibacterium bergeronii, Ureaplasma urealyticum, Mycoplasma genitalium, Parvimonas micra, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, Bacteroides fragdis, Clostridium septicum, Clostridium perff ingens, Clostridium difficile, Clostridium tertium, Fusobacterium mortiferum, Peptoanaerobacter stomatis, Clostridioides difficile, Streptococcus gallolyticus, Helicobacter pylori, Treponema pallidum, Treponema denticola, Borreliella burgdorferi, Borreliella bavariensis, Borreliella garinii, Borrelia garinii, Borrelia spielmanii, Borrelia californiensis, Borrelia bissettiae, Borrelia burgdorferi, Borrelia genomospecies, Borrelia lanei, Borrelia sinica, Borrelia mayonii, Borrelia lusitaniae, Borrelia kurtenbachii, Borrelia andersonii, Borrelia coriaceae, Borrelia nietonii, Borrelia afzelii, Borrelia spielmanii, Borrelia hermsii, Borrelia turcica, Borrelia miyamotoi, Bacteroides ovatus, Brachyspira hyodysenteriae , Gardnerella vaginalis, Gardnerella leopoldii, Leptospira biflexa, Mor axe Ila catarrhalis, Parabacteroides merdae, Sneathia amnii, and Neisseria gonorrhoeae.

9. The method of any one of claims 1 to 5, wherein the bacterium has a genus selected from Staphylococcus, Streptococcus, and Enterococcus.

10. The method of any one of claim 1 to 5 or 9, wherein the bacterium is selected from Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dentisani, Streptoccocus mutans, Streptococcus salivarius, and Enterococcus faecalis.

11. The method of any one of claims 1 to 8, wherein the bacterium is an oral disease-associated bacterium selected from Fusobacterium nucleatum, Fusobacterium periodonticum, Fusobacterium necrophorum, Fusobacterium varium Porphyromonas gingivalis, Porphyromonas asaccharolytica, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Prevotella nigrescens, and Veillonella parvula.

12. The method of claim 11, wherein the oral disease-associated bacterium is selected from Fusobacterium nucleatum, Fusobacterium nucleatum subsp. animalis, Fusobacterium nucleatumsubsp. polymorphum, Fusobacterium periodonticum, Fusobacterium necrophorum, Fusobacterium varium ClindaR, Porphyromonas gingivalis, Porphyromonas gingivalis HG66, Porphyromonas gingivalis 84-3, Porphyromonas asaccharolytica, Aggregalibacter actinomycetemcomitans, Prevotella intermedia Prevotella nigrescens, and Veillonella parvula.

13. The method of any one of claims 1 to 10, wherein the bacterium is a bacterial vaginosis (BV)-associated bacterium or an endometriosis-associated bacterium selected from Gardnerella vaginalis, Gardnerella leopoldii, Prevotella bivia, Prevotella corporis, Streptococcus agalactiae, Mobiluncus curtisii, Atopobium vaginae, Criibacterium bergeronii, Fusobacterium nucleatum, Ureaplasma urealyticum, and Mycoplasma genitalium.

14. The method of any one of claims 1 to 10, wherein the bacterium is a colorectal cancer (CRC)-associated bacterium selected from Fusobacterium nucleatum, Parvimonas micra, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, Bacteroides fragilis, Clostridium septicum, Clostridium perjringens, Clostridium difficile, Fusobacterium mortiferum, Fusobacterium necrophorum, Peptoanaerobacter stomatis, Enterococcus faecalis, Enterococcus faecalis, Clostridioides difficile, Porphyromonas gingivalis, Porphyromonas asaccharolytica, Streptococcus gallolyticus, Veillonella parvula, Escherichia coli, and Staphylococcus aureus.

15. The method of claim 14, wherein the CRC-associated bacterium is selected from Fusobacterium nucleatum, Fusobacterium nucleatum subsp. animalis, Parvimonas micra DSM2046, Parvimonas micra ATCC 23195, Peptostreptococcus anaerobius, Peptostreptococcus stomatis, Bacteroides fragilis (ETBF), Clostridium septicum, Clostridium perjringens, Clostridium difficile, Fusobacterium nucleatum ATCC 25586, Fusobacterium nucleatum subsp. animalis ATCC 51191, Fusobacterium nucleatum subsp. vincent ATCC 49256, Fusobacterium nucleatum subsp . polymorphum ATCC 10953, Fusobacterium mortiferum ATCC 25557, Fusobacterium necrophorum ATCC 25286, Parvimonas micra DSM20468, Peptoanaerobacter stomatis DSM28705, Enterococcus faecalis, Vancomycin-resistant Enterococcus faecalis (VRE), Enterotoxigenic Bacteroides fragilis, Clostridioides difficile ATCC 9689, Porphyromonas gingivalis ATCC 33277, Porphyromonas gingivalis ATCC BAA-308, Porphyromonas asaccharolytica ATCC 25260, Porphyromonas asaccharolytica ATCC 27908,Streptococcus gallolyticus, Veillonella parvula ATCC 10790, Escherichia coli MG1655, and Staphylococcus aureus HG003.

16. The method of any one of claims 1 to 8, wherein the bacterium is a gastric cancer-associated bacterium or a gastritis-associated bacterium, wherein the gastric cancer-associated bacterium or the gastritis-associated bacterium is Helicobacter pylori.

17. The method of claim 16, wherein the gastric cancer-associated bacterium or the gastritis-associated bacterium is selected from Helicobacter pylori ATCC700392, Helicobacter pylori ATCC43504, Helicobacter pylori ATCC700684, and Helicobacter pylori SSI.

18. The method of any one of claims 1 to 8, wherein the bacterium is a syphilis-associated bacterium, wherein the syphilis-associated bacterium is Treponema pallidum.

19. The method of any one of claims 1 to 8, wherein the bacterium is a Lyme disease-associated bacterium selected from Borreliella burgdorferi, Borreliella bavariensis, and Borreliella garinii.

20. The method of claim 19, wherein the Lyme disease-associated bacterium is selected from Borreliella burgdorferi B31 , Borreliella burgdorferi N40, Borreliella bavariensis, and Borreliella garinii.

21. The method of any one of claims 1 to 8, wherein the bacterium is an episodic fever-associated bacterium or a relapsing fever (RF)-associated bacterium selected from Borrelia garinii, Borrelia spielmanii, Borrelia calif orniensis, Borrelia bissettiae, Borrelia burgdorferi, Borrelia genomospecies, Borrelia lanei, Borrelia sinica, Borrelia mayonii, Borrelia lusitaniae, Borrelia kurtenbachii, Borrelia andersonii, Borrelia coriaceae, Borrelia nietonii, Borrelia afzelii, Borrelia spielmanii, Borrelia hermsii, and Borrelia miyamotoi.

22. The method of claim 21, wherein the episodic fever-associated bacterium or the RF-associated bacterium is selected from Borrelia garinii subsp. garinii DSM 10534, Borrelia spielmanii DSM 16813, Borrelia californiensis DSM 17989, Borrelia bissettiae DSM 17990, Borrelia burgdorferi DSM 4681, Borrelia genomospecies DSM 17991, Borrelia lanei DSM 17992, Borrelia sinica DSM 23262, Borrelia mayonii DSM 102811, Borrelia lusitaniae DSM107168, Borrelia kurtenbachii ATCC BAA-2495, Borrelia andersonii ATCC 700555, Borrelia coriaceae ATCC 43381, Borrelia nietonii TSD-355, Borrelia afzelii ATCC 51992, Borrelia spielmanii DSM 16813, Borrelia hermsii HS1, Borrelia hermsii DAH, and Borrelia miyamotoi ATCC BAA-3151.

23. The method of any one of claims 1 to 8, wherein the bacterium is a gonorrhea-associated bacterium, wherein the gonorrhea-associated bacterium is Neisseria gonorrhoeae.

24. The method of claim 23, wherein the gonorrhea-associated bacterium is selected from Neisseria gonorrhoeae FA 1090 and Neisseria gonorrhoeae MS11.

25. The method of any one of claims 1 to 8, wherein the bacterium is Fusobacterinm nude alum.

26. The method of any one of claims 1 to 8, wherein the bacterium is Porphyromonas gingivalis.

27. The method of claim 25 or 26, wherein the treatment treats or prevents cardiovascular disease.

28. The method of claim 27, wherein the cardiovascular disease is heart failure.

29. A method of treating a disease or disorder selected from acute bacterial sinusitis, acute otitis media, an anaerobic infection, bacteremia, bacterial vaginosis, cancer, cellulitis, chorioamnionitis, colitis, COPD exacerbations, dental caries, diarrhea, endocarditis, endometriosis, episodic fever, food poisoning, gas gangrene, gonorrhea, hemolytic uremic syndrome, impetigo, intra-abdominal abscess, intra-abdominal infections, Lemierre’s syndrome, Lyme disease, Lyme neuroborreliosis, maternal peripartum infections, meningitis, myonecrosis, neonatal early-onset sepsis, nongonococcal urethritis, odontogenic infections, opportunistic infections, osteomyelitis, pelvic inflammatory disease, peptic ulcer disease, peptoanaerobacter stomatis, periodontitis, peritonitis, pneumonia , purulent pericarditis, relapsing fever, sepsis, soft tick relapsing fever, syphilis, toxic shock syndrome, and urinary tract infection, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (La):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C > alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

30. The method of claim 29, wherein the disease or disorder is a cancer is selected from colorectal cancer, gastric cancer, and gastric MALT lymphoma.

31. The method of claim 29 or 30, wherein the disease or disorder is colorectal cancer.

32. The method of any one of claims 29 to 31, wherein the disease or disorder is a cancer, wherein the subject is resistant or refractory to chemotherapy, radiotherapy, and / or immunotherapy.

33. The method of claim 29, wherein the disease or disorder is periodontal disease, optionally periodontitis.

34. The method of claim 29, wherein the disease or disorder is Lyme disease, optionally neuroborreliosis.

35. The method of claim 29, wherein the disease or disorder is a peptic ulcer.

36. The method of claim 29, wherein the disease or disorder is bacterial vaginosis.

37. The method of claim 29, wherein the disease or disorder is endometriosis.

38. The method of claim 29, wherein the disease or disorder is a urinary tract infection.

39. A method of increasing efficacy of chemotherapy, radiotherapy, and / or immunotherapy treatment, comprising administering to a subject a therapeutically effective amount of a compound of Formula (La):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionallysubstituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cx-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

40. A method of preventing plaque buildup or atherosclerosis, comprising administering to a subject a therapeutically effective amount of a compound of Formula (I-a):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

41. The method of claim 40, wherein the subject has a Porphyromonas gingivalis infection.

42. The method of any one of the preceding claims, wherein the treatment has no or substantially no effect on gut microbiome.

43. The method of any one of the preceding claims, wherein the treatment has no or substantially no inhibition effect on gut commensal bacteria.

44. The method of claim 43, wherein the gut commensal bacteria comprise Bifidobacterium longum, Bifidobacterium bifidum, Bifobacterium animalis, Bifobacterium dentium, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus paracasei, Lactobacillus iners, Ligilactobacillus salivarius, Blautia producta, Akkermansia muciniphila, and / or Roseburia hominis.

45. The method of any one of the preceding claims, wherein the treatment preserves the symbiotic microbiome of the oral, gastrointestinal, and / or vaginal environments.

46. The method of any one of the preceding claims, wherein the treatment selectively targets pathogenic microorganisms while maintaining the integrity of the symbiotic microbiome in the oral, gut, and / or vaginal ecosystems.

47. The method of any one of the preceding claims, wherein the treatment reduces disruption of gut commensal bacteria relative to treatment with a broad spectrum antibiotic.

48. The method of any one of the preceding claims, wherein the treatment reduces or delays the emergence of antibiotic resistance relative to treatment with a broad spectrum antibiotic.

49. A coating for hospital equipment comprising a compound of Formula (I-a):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein in Formula (I-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted -C10 aryl, optionally substituted 5- to 12-membered heteroaryl, optionallysubstituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;X1and X2are each independently a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

50. The coating of claim 49, wherein the hospital equipment is a catheter.

51. The method of any one of claims 1 to 48 or the coating of claim 49 or 50, wherein X1is a moiety comprising one or more groups selected from -C(O)-, -C(O)NH-, and optionally substituted C1-C4 alkylene.

52. The method of any one of claims 1 to 48 or 51 or the coating of any one of claims 49 toR3is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-CG alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6; andy is an integer of 1 or 2.

53. The method of any one of claims 1 to 48, 51, or 52 or the coating of any one of claims 49 to 52, wherein the compound has a structure according to Formula (TT-a):wherein in Formula (Il-a):R1and R2are each independently selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R3is selected from H, -ORa, -C(O)Ra, -C(O)ORa, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl;X2is a moiety comprising one or more groups selected from -O-, -S-, -NRa-, -C(O)-, -C(O)NRa-, -NRaC(O)-, optionally substituted Ci-Ce alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, and optionally substituted 3- to 8-membered heteroalkylene;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, 5, and 6;y is an integer of 1 or 2;ring A is selected from optionally substituted arylene, optionally substituted cycloalkylene, optionally substituted heteroarylene, and optionally substituted heterocycloalkylene; andring B is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.

54. The method of any one of claims 1 to 48 or 51 to 53 or the coating of any one of claims 49 to 53, wherein X2is optionally substituted C1-C4 alkylene.

55. The method of any one of claims 1 to 48 or 51 to 54 or the coating of any one of claims 49 to 54, wherein X2is optionally substituted C1-C2 alkylene.

56. The method of any one of claims 1 to 48 or 51 to 55 or the coating of any one of claims 49 to 55, wherein ring A is optionally substituted 3- to 8-membered heterocycloalkylene.

57. The method of any one of claims 1 to 48 or 51 to 56 or the coating of any one of claims49 to 56, wherein ring A isand ring A is optionally substituted.

58. The method of any one of claims 1 to 48 or 51 to 57 or the coating of any one of claims 49 to 57, wherein ring B is an optionally substituted 3- to 8-membered aryl ring fused to an optionally substituted 3- to 8-membered heterocycloalkyl ring.

59. The method of any one of claims 1 to 48 or 51 to 58 or the coating of any one of claims49 to 58, wherein ring B isand ring B is optionally substituted.

60. The method of any one of claims 1 to 48 or 51 to 59 or the coating of any one of claims 49 to 59, wherein the compound has a structure according to Formula (Ill-a):wherein in Formula (Ill-a):R1and R2are independently at each occurrence selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Cs-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Ca-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R3is selected from H, -ORa, -C(O)Ra, -C(O)ORa, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl;R4, R3, R6, R7, R8, R9, R10, R11, and R12are independently at each occurrence selected from H, halogen, -ORa, -N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted 3- to 6-membered heteroalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, and 5; andy is an integer of 1 or 2.

61. The method of any one of claims 52 to 60 or the coating of any one of claims 52 to 60, wherein R3is Ci-Ce alkyl.

62. The method of any one of claims 52 to 61 or the coating of any one of claims 52 to 61, wherein R3is t-butyl.

63. The method of any one of claims 60 to 62 or the coating of any one of claims 60 to 62, wherein one or more of R4, R5, R6, R7, R8, R9, R10, R11, and R12are H.

64. The method of any one of claims 60 to 63 or the coating of any one of claims 60 to 63, wherein R8is H.

65. The method of any one of claims 60 to 64 or the coating of any one of claims 60 to 64, wherein R4, R5, R6, R7, R9, R10, R11, and R12are H.

66. The method of any one of claims 1 to 48 or 51 to 65 or the coating of any one of claims 49 to 65, wherein the compound has a structure according to Formula (IV-a):R1is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -(CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C'3-Cx cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R2is selected from H, -(CH2)xORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Cx-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, and 5; andy is an integer of 1 or 2.

67. The method of any one of claims 1 to 48 or 51 to 66 or the coating of any one of claims 49 to 66, wherein R1is selected from H, -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Cs-Cio aryl, and x is selected from 0, 1, 2, 3, and 4.

68. The method of any one of claims 1 to 48 or 51 to 67 or the coating of any one of claims49 to 67, wherein R1is selected from69. The method of any one of claims 1 to 48 or 51 to 68 or the coating of any one of claims 49 to 68, wherein R1is H.

70. The method of any one of claims 1 to 48 or 51 to 68 or the coating of any one of claims 49 to 68, wherein R1is not H.

71. The method of any one of claims 1 to 48 or 51 to 70 or the coating of any one of claims 49 to 70, wherein R2is -(CH2)x-(C3-Ce cycloalkyl), and x is selected from 1, 2, 3, and 4.

72. The method of any one of claims 1 to 48 or 51 to 71 or the coating of any one of claims 49 to 71, wherein R2is -(CH2)-(cyclopentyl).

73. The method of any one of claims 1 to 48 or 51 to 70 or the coating of any one of claims 49 to 70, wherein R2is Ci-Ce alkyl.

74. The method of any one of claims 1 to 48 or 51 to 70 or 73 or the coating of any one of claims 49 to 70 or 73, wherein R2is 1-butyl.

75. The method of any one of claims 1 to 48 or 51 to 74 or the coating of any one of claims 49 to 74, wherein the compound has the structure of Compound 1001 or Compound 1019:Compound 1019.

76. The method of any one of claims 1 to 48 or 51 to 74 or the coating of any one of claims 49 to 74, wherein the compound has a structure of selected from any one of Compounds 1002-1018 and 1020-1036.Compound 1003Compound 1007DBl / 167011927.11Compound 1010Compound 1012DBl / 167011927.11Compound 1015Compound 1016DB1 / 167011927.11Compound 1020Compound 1021DBl / 167011927.11Compound 1025DBl / 167011927.11Compound 1028Compound 1030DB1 / 167011927.11Compound 1033Compound 1036.

77. The method of any one of claims 1 to 48 or 51 to 76 or the coating of any one of claims 49 to 76, wherein the compound is administered in the form of a pharmaceutically acceptable composition.

78. The method of claim 77, wherein the pharmaceutically acceptable composition comprises at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

79. A compound of Formula (IV-b):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, or cocrystal thereof, wherein in Formula (IV-b):R1is selected from -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - (CH2)xOC(O)N(Ra)2, -C(O)N(Ra)S(O)yRa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionallysubstituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;R2is selected from H, -(CH2)xORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Cs haloalkyl, optionally substituted C -Cs cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ce-Cio aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;x is independently at each occurrence selected from 0, 1, 2, 3, 4, and 5; andy is an integer of 1 or 2.

80. The compound of claim 79, wherein R1is selected from -(CH2)xORa, -(CH2)xOC(O)Ra, -C(O)Ra, -C(O)ORa, -C(O)(CH2)xC(O)Ra, -P(O)(ORa)2, optionally substituted Ci-C6alkyl, optionally substituted Ci-Ce haloalkyl, and optionally substituted Ce-Cio aryl, and x is selected from 0, 1, 2, 3, and 4.

81. The compound of claim 79 or 80, wherein R1is selected from82. The compound of any one of claims 79 to 81, wherein R2is -(CH2)x-(C3-Ce cycloalkyl), and x is selected from 1, 2, 3, and 4.

83. The compound of any one of claims 79 to 82, wherein R2is -(CH2)-(cyclopentyl).

84. The compound of any one of claims 79 to 81, wherein R2is Ci-Ce alkyl.

85. The compound of any one of claims 79 to 81 or 84, wherein R2is 1-butyl.

86. A compound of Formula (IV-b):or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, or cocrystal thereof, wherein in Formula (IV-b):R2is -(CH2)-(cyclopentyl) or 1-butyl.

87. The compound of any one of claims 79 to 86, wherein the compound has a structure of selected from any one of Compounds 1002-1018:Compound 1002Compound 1005Compound 1006DBl / 167011927.11Compound 1014DBl / 167011927.11Compound 1017Compound 1022Compound 1026DBl / 167011927.11Compound 1031DBl / 167011927.11Compound 1036.

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