ANTIMICROBIAL AGENTS AND COMPOSITIONS AND USES THEREOF

Described herein are compounds that act as antimicrobial agents, compositions comprising these compounds, and methods of their use in to treating infections caused by Helicobacter pylori (H. pylori) or killing or inhibiting the growth of H. pylori.

BACKGROUND

Helicobactor pylori(H. pylori) is a gram-negative, microaerophilic bacterium that colonizes in the gastric mucosa of its host.H. pyloriinfection is widespread with seroprevalence in the developed world between 30-60%. Infection with the bacterium is usually contracted during childhood and patients remain infected for life unless treated.H. pyloriinfection has been shown to result in the development of gastritis, peptic ulcer, and mucosa-associated lymphoid tissue (MALT) lymphoma and has been linked to gastric adenocarcinoma. Drug resistance is prevalent in clinical isolates ofH. pylori.Antibiotics with new targets and mechanisms of action are needed to treatH. pyloriinfections. New antimicrobial agents are needed to treat infections caused byH. pylori.

SUMMARY

Provided herein, in part, are compounds that can be used as antimicrobial agents in the inhibition of the growth or killing ofH. pyloriand treatment of infections and disorders associated withH. pylori,such as gastrointestinal disorders. In some embodiments, theH. pyloricomprises a group of strains. In some embodiments, theH. pyloriis resistant to at least one drug (e.g. multidrug-resistantH. pylori).

In one aspect, described herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, substituted or unsubstituted C1-6alkyl (e.g., —CH3, —CH2CH3, C1-6haloalkyl, substituted or substituted aralkyl, e.g., substituted or unsubstituted benzyl), substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl); R2is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl), or —N═C—RZ1, wherein —N═CZ1can exist in the E or Z configuration and RZ1is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl); X is nitrogen or oxygen, wherein when X is nitrogen p is 2; and when X is oxygen p is 1; p is 1 or 2, wherein when p is 2, R1can be taken together with N attached to two instances of R1to form a 3-6 membered heterocylyl; and q is 0 or 1.

Also described herein is a method of treating an infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, substituted or unsubstituted C1-6alkyl (e.g., —CH3, —CH2CH3, C1-6haloalkyl, substituted or substituted aralkyl, e.g., substituted or unsubstituted benzyl), substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl); R2is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl), or —N═C—RZ1, wherein —N═C—RZ1can exist in the E or Z configuration and RZ1is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl); X is nitrogen or oxygen, wherein when X is nitrogen p is 2; and when X is oxygen p is 1; p is 1 or 2, wherein when p is 2, R1can be taken together with N attached to two instances of R1to form a 3-6 membered heterocylyl; and q is 0 or 1.

Also described herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a a therapeutically effective amount compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, substituted or unsubstituted C1-6alkyl (e.g., —CH3, —CH2CH3, C1-6haloalkyl, substituted or substituted aralkyl, e.g., substituted or unsubstituted benzyl), substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl); R2is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl), or —N═C—RZ1, wherein —N═C—RZ1can exist in the E or Z configuration and RZ1is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl); X is nitrogen or oxygen, wherein when X is nitrogen p is 2; and when X is oxygen p is 1; p is 1 or 2, wherein when p is 2, R1can be taken together with N attached to two instances of R1to form a 3-6 membered heterocylyl; and q is 0 or 1.

Further described herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II)

or pharmaceutically acceptable salt thereof, wherein:represents a single or a double bond as valency permits; R5is hydrogen or oxygen; R6is selected from the group consisting of hydrogen, oxygen, and substituted or unsubstituted C1-6alkyl, provided that, when R5is oxygen R6is oxygen as valency permits; Y is carbon or nitrogen; Z is oxygen or sulfur; R7is oxygen or nitrogen, wherein the nitrogen is substituted with —NHC(O)NH2, —NHC(O)C1-6alkyl, —C(O)OH, or —C(O)O C1-6alkyl; and R8is hydrogen, substituted or unsubstituted C1-6alkyl, or —OH, wherein R7and R8can be taken together to form a substituted or unsubstituted 5-membered heteroaryl.

Also described herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (III)

or pharmaceutically acceptable salt thereof, wherein:represents a single or a double bond as valency permits, wherein whenis a single bond the nitrogen is substituted with hydrogen; R9is 5-7 membered heteroaryl optionally substituted with —NO2, —NH2, or halogen whenis a double bond; and whenis a single bond, R9is oxo; and R10is hydrogen or C1-6alkenyl optionally substituted with substituted or unsubstituted aryl whenis a single bond.

Also described herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (IV)

or pharmaceutically acceptable salt thereof, wherein: X′ is carbon or phosphorus; R11is each and independently selected from the group consisting of substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6alkoxy, —NHC1-6alkyl, —NHC6H5, and C1-6alkenyl, wherein the alkenyl is optionally substituted with substituted or unsubstituted 5-7 membered aryl; and t is 1 or 2, wherein t is 1 when X′ is carbon; and when X′ is phosphorous t is 2.

Also described herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound of Formula (II):

or pharmaceutically acceptable salt thereof, wherein:represents a single or a double bond as valency permits; R5is hydrogen or oxygen; R6is selected from the group consisting of hydrogen and substituted or unsubstituted C1-6alkyl, provided that, when R5is oxygen R6is oxygen as valency permits; Y is carbon or nitrogen; Z is oxygen or sulfur; R7is oxygen or nitrogen, wherein the nitrogen is substituted with —NHC(O)NH2, —NHC(O)C1-6alkyl, —C(O)OH, or —C(O)O—C1-6alkyl; and R8is hydrogen, substituted or unsubstituted C1-6alkyl, or —OH, wherein R7and R8can be taken together to form a substituted or unsubstituted 5-membered heteroaryl.

Additionally described herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound of Formula (III):

or pharmaceutically acceptable salt thereof, wherein:represents a single or a double bond as valency permits, wherein whenis a single bond the nitrogen is substituted with hydrogen; R9is 5-7 membered heteroaryl optionally substituted with —NO2, —NH2, or halogen whenis a double bond; and whenis a single bond, R9is oxo; and R10is hydrogen or C1-6alkenyl optionally substituted with substituted or unsubstituted aryl whenis a single bond.

Additionally described herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound of Formula (IV):

or pharmaceutically acceptable salt thereof, wherein: X′ is carbon or phosphorus; R11is each and independently selected from the group consisting of substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6alkoxy, —NHC1-6alkyl, —NHC6H5, and C1-6alkenyl, wherein the alkenyl is optionally substituted with substituted or unsubstituted 5-7 membered aryl; and t is 1 or 2, wherein t is 1 when X′ is carbon; and when X′ is phosphorous t is 2.

Additionally provided herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound selected from the group consisting of a compound of Table 1 provided below and pharmaceutically acceptable salts thereof.

Additionally provided herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of a compound of Table 1 provided below and pharmaceutically acceptable salts thereof.

Additionally provided herein is a method of killing or inhibiting the growth ofH. pylori,comprising contactingH. pyloriwith a composition comprising an effective amount of a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Table 1, or pharmaceutically acceptable salt thereof.

Additionally provided herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Table 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

The compounds and compositions described herein can be antimicrobial agents that kill and/or inhibit the growth of strains ofH. pylori,includingH. pyloriresistant to at least one known drug. In some embodiments, the compounds or compositions can be used the treat a gastrointestinal infection in a subject caused by strains ofH. pylori.

Compounds

One feature of the present disclosure relates to compounds that act as antimicrobial agents againstH. pylori.For example, disclosed is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, substituted or unsubstituted C1-6alkyl (e.g., —CH3, —CH2CH3, C1-6haloalkyl, substituted or substituted aralkyl, e.g., substituted or unsubstituted benzyl), substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl); R2is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl), or —N=C—RZ1, wherein —N═C—RZ1can exist in the E or Z configuration and RZ1is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl); X is nitrogen or oxygen, wherein when X is nitrogen p is 2; and when X is oxygen p is 1; p is 1 or 2, wherein when p is 2, R1can be taken together with N attached to two instances of R1to form a 3-6 membered heterocylyl; and q is 0 or 1.

In some embodiments, R3is —CH3and n is 1. In some embodiments, R3is —OCH3and n is 1. In some embodiments, R3is —Cl and n is 1 or 2. In some embodiments, R3is —Cl and n is 1. In some embodiments, R3is —Cl and n is 2. In some embodiments, R3is not halo. In some embodiments, n is 0.

Also featured herein is a compound of Formula (II):

whereinrepresents a single or a double bond as valency permits; R5is hydrogen or oxygen; R6is selected from the group consisting of hydrogen, oxygen, and substituted or unsubstituted C1-6alkyl, provided that, when R5is oxygen R6is oxygen as valency permits; Y is carbon or nitrogen; Z is oxygen or sulfur; R7is oxygen or nitrogen, wherein the nitrogen is substituted with —NHC(O)NH2, —NHC(O) C1-6alkyl, —C(O)OH, or —C(O)O C1-6alkyl; and R8is hydrogen, substituted or unsubstituted C1-6alkyl, or —OH, wherein R7and R8can be taken together to form a substituted or unsubstistuted 5-membered heteroaryl.

In some embodiments, Y is nitrogen and Z is sulfur. In some embodiments, R7and R8can be taken together to form a substituted or unsubstituted 5-membered heteroaryl, e.g., furnayl.

Also featured herein is a compound of Formula (III):

whereinrepresents a single or a double bond as valency permits, wherein whenis a single bond the nitrogen is substituted with hydrogen; R9is 5-7 membered heteroaryl optionally substituted with —NO2, —NH2, or halogen whenis a double bond; and whenis a single bond, R9is oxo; and R10is hydrogen or C1-6alkenyl optionally substituted with substituted or unsubstituted aryl whenis a single bond.

Also featured herein is a compound of Formula (IV):

wherein X′ is carbon or phosphorus; R11is each and independently selected from the group consisting of substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6alkoxy, —NHC1-6alkyl, —NHC6H5, and C1-6alkenyl, wherein the alkenyl is optionally substituted with substituted or unsubstituted 5-7 membered aryl; and t is 1 or 2, wherein t is 1 when X′ is carbon; and when X′ is phosphorous t is 2.

In some embodiments, X′ is phosphorus. In some embodiments, R11is each and independently selected from the group consisting of substituted or unsubstituted C1-6alkoxy, and —NHC6H5. In some embodiments, R11is each and independently selected from the group consisting of substituted or unsubstituted ethoxy (e.g., unsubstituted ethoxy), and —NHC6H5.

In an embodiment, the compound is a compound shown in Table 1.

Methods of Use

Compounds and compositions described herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), Table 1, or a pharmaceutically acceptable salt thereof or a composition comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Table 1, or a pharmaceutically acceptable salt thereof) can be used to kill and/or inhibit the growth of a gram-negative bacterium such asH. pylori.In some embodiments,H. pyloricomprises a group of strains. In some embodiments, the strain ofH. pyloriis selected from 49503, 43504, and 51932. In some embodiments,H. pyloriis resistant to at least one known drug.

The methods can be used to treat or prevent a infection in a subject in need thereof. Compounds and compositions described herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), Table 1, or a pharmaceutically acceptable salt thereof or a composition comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Table 1, or a pharmaceutically acceptable salt thereof) can be used to treat an infection caused by a gram-negative bacterium such asH. pylori.In some embodiments,H. pyloricomprises a group of strains. In some embodiments, the strain ofH. pyloriis selected from 49503, 43504, and 51932. In some embodiments,H. pyloriis resistant to at least one known drug. In some embodiments, the infection is a nosocomial infection. In some embodiments, the infection is a community-acquired infection.

In some embodiments, the infection is a gastrointestinal infection. In some embodiments, the gastrointestinal infection is caused by a gram-negative bacterium. In some embodiments, the gastrointestinal gram-negative bacterium that causes the gastrointestinal infection isH. pylori.In some embodiments, theH. pylorithat causes the gastrointestinal infection is resistant to at least one known drug. In some embodiments, the gastrointestinal infection is caused by a bacterium.

In some embodiments, the gastrointestinal infection is a nosocomial infection. In some embodiments, the gastrointestinal infection is a community-acquired infection.

In some embodiments, the gastrointestinal infection can be treated or prevented by administering to the subject a compound or composition described herein.

In some embodiments, the gastrointestinal infection is a stomach infection. In some embodiments, the gastrointestinal infection is a peptic ulcer. In some embodiments, the gastrointestinal infection is a gastric ulcer. In some embodiments, the gastrointestinal infection is a duodenal ulcer. In some embodiments, the gastrointestinal infection is gastritis. In some embodiments, the gastrointestinal infection is chronic gastritis. In some embodiments, the gastrointestinal infection is gastric mucosal inflammation.

The compounds described herein can be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, or applied to an object to treat or prevent a variety of bacterial infection, including those described herein below. In some embodiments, the compounds and/or compositions inhibit the growth of bacteria and/or decrease bacterial load in a subject or on an object.

In some embodiments, the compounds described herein or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional agent. In some embodiments, the additional agent is an antibiotic. In some embodiments, the additional agent is an antibiotic selected from the group consisting of an amoxicillin, tetracyline, metronidazole, or clarithromycin. In some embodiments, the additional agent is an amoxicillin. In some embodiments, the additional agent is a clarithromycin. In some embodiments, the additional agent is an acid suppressor. In some embodiments, the additional agent is an acid suppressor selected from the group consisting of omeprazole, pantoprazole, ranitidine bismuth citrate, and bismuth subsalicylate. In some embodiments, the additional agent is an acid suppressor is omeprazole. In some embodiments, the additional agent is an acid suppressor is pantoprazole.

In some embodiments, the method used to treat or prevent a gastrointestinal infection in a subject further comprises contactingH. pylori,with at least one other anti-microbial agent. In some embodiments, the anti-microbial agent is an anti-microbial peptide. In some embodiments, the anti-microbial peptide is β-defensin. In some embodiments, the additional agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, and combinations of two or more thereof. In some embodiments, the additional agent is an aminoglycoside antibiotic. In some embodiments, the additional agent is gentamicin. In some embodiments, the additional agent is cationic antimicrobial peptide (CAMP).

In some embodiments, the compounds described herein or a pharmaceutically acceptable salt thereof and the additional agent are administered consecutively. In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof and the additional agent are administered simultaneously.

Additional methods of use provided by the present disclosure include the following:

In one aspect, described herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, substituted or unsubstituted C1-6alkyl (e.g., —CH3, —CH2CH3, C1-6haloalkyl, substituted or substituted aralkyl, e.g., substituted or unsubstituted benzyl), substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl); R2is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl), or —N═C—RZ1, wherein —N═C—RZ1can exist in the E or Z configuration and RZ1is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl); X is nitrogen or oxygen, wherein when X is nitrogen p is 2; and when X is oxygen p is 1; p is 1 or 2, wherein when p is 2, R1can be taken together with N attached to two instances of R1to form a 3-6 membered heterocylyl; and q is 0 or 1.

In some embodiments, theH. pyloriis a group of strains. In some embodiments, the strain is selected from the group consisting of 49503, 43504, and 51932. In some embodiments, the strain is 49503. In some embodiments, the strain is 43504. In some embodiments, the strain is 51932. In some embodiments, the killing or inhibiting the growth ofH. pyloriis in vivo, of in a body of a subject. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional agent. In some embodiments, the additional agent is an antibiotic. In some embodiments, the additional agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, amoxicillin, tetracycline, metronidazole, clarithromycin and combinations of two or more thereof. In some embodiments, the additional agent is an antibiotic is amoxicillin. In some embodiments, the additional agent is an antibiotic is clarithromycin. In some embodiments, the additional agent is an acid suppressor. In some embodiments, the additional agent is an acid suppressor selected from the group consisting of omeprazole, pantoprazole, ranitidine bismuth citrate, and bismuth subsalicylate. In some embodiments, the additional agent is an acid suppressor is omeprazole. In some embodiments, the additional agent is an acid suppressor is pantoprazole. In some embodiments, the additional agent is an anti-microbial agent. In some embodiments, the anti-microbial agent is niclosamide. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional agent are administered consecutively. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional agent are administered simultaneously.

In some embodiments, R3is —CH3and n is 1. In some embodiments, R3is —OCH3and n is 1. In some embodiments, R3is —Cl and n is 1 or 2. In some embodiments, R3is —Cl and n is 1. In some embodiments, R3is —Cl and n is 2. In some embodiments, n is 0.

Also described herein is a method of treating an infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, substituted or unsubstituted C1-6alkyl (e.g., —CH3, —CH2CH3, C1-6haloalkyl, substituted or substituted aralkyl, e.g., substituted or unsubstituted benzyl), substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl); R2is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl), or —N═C—RZ1, wherein —N═C—RZ1can exist in the E or Z configuration and RZ1is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl); X is nitrogen or oxygen, wherein when X is nitrogen p is 2; and when X is oxygen p is 1; p is 1 or 2, wherein when p is 2, R1can be taken together with N attached to two instances of R1to form a 3-6 membered heterocylyl; and q is 0 or 1.

In some embodiments, R3is —CH3and n is 1. In some embodiments, R3is —OCH3and n is 1. In some embodiments, R3is —Cl and n is 1 or 2. In some embodiments, R3is —Cl and n is 1. In some embodiments, R3is —Cl and n is 2. In some embodiments, n is 0.

In some embodiments, the infection is a bloodstream infection. In some embodiments, the infection is a respiratory infection. In some embodiments, the respiratory infection is pneumonia. In some embodiments, the infection is osteomyelitis. In some embodiments, the infection is endocarditis. In some embodiments, the infection is cellulitis. In some embodiments, the infection is meningitis. In some embodiments, the infection is the result of a wound. In some embodiments, the wound is a surgical wound. In some embodiments, the wound is an ulcer. In some embodiments, the ulcer is a pressure ulcer. In some embodiments, the infection is a urinary tract infection. In some embodiments, the wound is a skin abscess. In some embodiments, the wound is a traumatic wound. In some embodiments, the infection is a community-acquired infection. In some embodiments, the infection is a nosocomial infection. In some embodiments, the composition is administered orally, intranasally, intramuscularly, intravenously, subcutaneously, or transdermally. In some embodiments, the composition is administered to the subject chronically or acutely. In some embodiments, the composition is administered to the subject in a single dose per day. In some embodiments, the composition is administered to the subject in multiple doses per day (e.g., 1, 2, 3, 4, or 5 times per day). In some embodiments, the composition is administered to the subject for 1, 2, 5, or 10 days. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is an antibiotic. In some embodiments, the additional therapeutic agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, and combinations of two or more thereof. In some embodiments, the additional therapeutic agent is an aminoglycoside antibiotic. In some embodiments, the additional therapeutic agent is gentamicin. In some embodiments, the additional therapeutic agent is cationic antimicrobial peptide (CAMP). In some embodiments, the cationic antimicrobial peptide is defensin 1. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered consecutively. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously.

Also described herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, substituted or unsubstituted C1-6 alkyl (e.g., —CH3, —CH2CH3, C1-6haloalkyl, substituted or substituted aralkyl, e.g., substituted or unsubstituted benzyl), substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl); R2is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl), or —N═C—RZ1, wherein —N═C—RZ1can exist in the E or Z configuration and RZ1is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (e.g., 3 to 8-membered cycloalkyl), or substituted or unsubstituted heterocyclyl (e.g., 3 to 8-membered heterocyclyl); X is nitrogen or oxygen, wherein when X is nitrogen p is 2; and when X is oxygen p is 1; p is 1 or 2, wherein when p is 2, R1can be taken together with N attached to two instances of R1to form a 3-6 membered heterocylyl; and q is 0 or 1.

In some embodiments, theH. pyloriis a group of strains. In some embodiments, the strain is selected from the group consisting of 49503, 43504, and 51932. In some embodiments, the strain is 49503. In some embodiments, the strain is 43504. In some embodiments, the strain is 51932. In some embodiments, the gastrointestinal infection is stomach infection. In some embodiments, the gastrointestinal infection is peptic ulcer. In some embodiments, the gastrointestinal infection is gastric ulcer. In some embodiments, the gastrointestinal infection is duodenal ulcer. In some embodiments, the gastrointestinal infection is gastritis. In some embodiments, the gastrointestinal infection is chronic gastritis. In some embodiments, the gastrointestinal infection is gastric mucosal inflammation. In some embodiments, the composition is administered orally, intranasally, intramuscularly, intravenously, subcutaneously, or transdermally. In some embodiments, the killing or inhibiting the growth ofH. pyloriis in vivo, of in a body of a subject. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional agent. In some embodiments, the additional agent is an antibiotic. In some embodiments, the additional agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, amoxicillin, tetracycline, metronidazole, clarithromycin and combinations of two or more thereof. In some embodiments, the additional agent is an antibiotic is amoxicillin. In some embodiments, the additional agent is an antibiotic is clarithromycin. In some embodiments, the additional agent is an acid suppressor. In some embodiments, the additional agent is an acid suppressor is omeprazole. In some embodiments, the additional agent is an acid suppressor is pantoprazole. In some embodiments, the additional agent is an anti-microbial agent. In some embodiments, the anti-microbial agent is niclosamide. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional agent are administered consecutively. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional agent are administered simultaneously.

In some embodiments, R3is —CH3and n is 1. In some embodiments, R3is —OCH3and n is 1. In some embodiments, R3is —Cl and n is 1 or 2. In some embodiments, R3is —Cl and n is 1. In some embodiments, R3is —Cl and n is 2. In some embodiments, n is 0.

Further described herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II)

or pharmaceutically acceptable salt thereof, wherein:represents a single or a double bond as valency permits; R5is hydrogen or oxygen; R6is selected from the group consisting of hydrogen, oxygen, and substituted or unsubstituted C1-6alkyl, provided that, when R5is oxygen R6is oxygen as valency permits; Y is carbon or nitrogen; Z is oxygen or sulfur; R7is oxygen or nitrogen, wherein the nitrogen is substituted with —NHC(O)NH2, —NHC(O) C1-6alkyl, —C(O)OH, or —C(O)O C1-6alkyl; and R8is hydrogen, substituted or unsubstituted C1-6alkyl, or —OH, wherein R7and R8can be taken together to form a substituted or unsubstituted 5-membered heteroaryl.

In some embodiments, theH. pyloriis a group of strains. In some embodiments, the strain is selected from the group consisting of 49503, 43504, and 51932. In some embodiments, the strain is 49503. In some embodiments, the strain is 43504. In some embodiments, the strain is 51932. In some embodiments, the gastrointestinal infection is stomach infection. In some embodiments, the gastrointestinal infection is peptic ulcer. In some embodiments, the gastrointestinal infection is gastric ulcer. In some embodiments, the gastrointestinal infection is duodenal ulcer. In some embodiments, the gastrointestinal infection is gastritis. In some embodiments, the gastrointestinal infection is chronic gastritis. In some embodiments, the gastrointestinal infection is gastric mucosal inflammation. In some embodiments, the composition is administered orally, intranasally, intramuscularly, intravenously, subcutaneously, or transdermally. In some embodiments, the killing or inhibiting the growth ofH. pyloriis in vivo, of in a body of a subject. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional agent. In some embodiments, the additional agent is an antibiotic. In some embodiments, the additional agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, amoxicillin, tetracycline, metronidazole, clarithromycin and combinations of two or more thereof. In some embodiments, the additional agent is an antibiotic is amoxicillin. In some embodiments, the additional agent is an antibiotic is clarithromycin. In some embodiments, the additional agent is an acid suppressor. In some embodiments, the additional agent is an acid suppressor is omeprazole. In some embodiments, the additional agent is an acid suppressor is pantoprazole. In some embodiments, the additional agent is an anti-microbial agent. In some embodiments, the anti-microbial agent is niclosamide.

Also described herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (III)

or pharmaceutically acceptable salt thereof, wherein:represents a single or a double bond as valency permits, wherein whenis a single bond the nitrogen is substituted with hydrogen; R9is 5-7 membered heteroaryl optionally substituted with —NO2, —NH2, or halogen whenis a double bond; and whenis a single bond, R9is oxo; and R10is hydrogen or C1-6alkenyl optionally substituted with substituted or unsubstituted aryl whenis a single bond.

In some embodiments, theH. pyloriis a group of strains. In some embodiments, the strain is selected from the group consisting of 49503, 43504, and 51932. In some embodiments, the strain is 49503. In some embodiments, the strain is 43504. In some embodiments, the strain is 51932. In some embodiments, the gastrointestinal infection is stomach infection. In some embodiments, the gastrointestinal infection is peptic ulcer. In some embodiments, the gastrointestinal infection is gastric ulcer. In some embodiments, the gastrointestinal infection is duodenal ulcer. In some embodiments, the gastrointestinal infection is gastritis. In some embodiments, the gastrointestinal infection is chronic gastritis. In some embodiments, the gastrointestinal infection is gastric mucosal inflammation. In some embodiments, the composition is administered orally, intranasally, intramuscularly, intravenously, subcutaneously, or transdermally. In some embodiments, the killing or inhibiting the growth ofH. pyloriis in vivo, of in a body of a subject. In some embodiments, the compound of Formula (III) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional agent. In some embodiments, the additional agent is an antibiotic. In some embodiments, the additional agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, amoxicillin, tetracycline, metronidazole, clarithromycin and combinations of two or more thereof. In some embodiments, the additional agent is an antibiotic is amoxicillin. In some embodiments, the additional agent is an antibiotic is clarithromycin. In some embodiments, the additional agent is an acid suppressor. In some embodiments, the additional agent is an acid suppressor is omeprazole. In some embodiments, the additional agent is an acid suppressor is pantoprazole. In some embodiments, the additional agent is an anti-microbial agent. In some embodiments, the anti-microbial agent is niclosamide.

Also described herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (IV)

or pharmaceutically acceptable salt thereof, wherein: X′ is carbon or phosphorus; R11is each and independently selected from the group consisting of substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6alkoxy, —NHC1-6alkyl, —NHC6H5, and C1-6alkenyl, wherein the alkenyl is optionally substituted with substituted or unsubstituted 5-7 membered aryl; and t is 1 or 2, wherein t is 1 when X′ is carbon; and when X′ is phosphorous t is 2.

In some embodiments, theH. pyloriis a group of strains. In some embodiments, the strain is selected from the group consisting of 49503, 43504, and 51932. In some embodiments, the strain is 49503. In some embodiments, the strain is 43504. In some embodiments, the strain is 51932. In some embodiments, the gastrointestinal infection is stomach infection. In some embodiments, the gastrointestinal infection is peptic ulcer. In some embodiments, the gastrointestinal infection is gastric ulcer. In some embodiments, the gastrointestinal infection is duodenal ulcer. In some embodiments, the gastrointestinal infection is gastritis. In some embodiments, the gastrointestinal infection is chronic gastritis. In some embodiments, the gastrointestinal infection is gastric mucosal inflammation. In some embodiments, the composition is administered orally, intranasally, intramuscularly, intravenously, subcutaneously, or transdermally. In some embodiments, the killing or inhibiting the growth ofH. pyloriis in vivo, of in a body of a subject. In some embodiments, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional agent. In some embodiments, the additional agent is an antibiotic. In some embodiments, the additional agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, amoxicillin, tetracycline, metronidazole, clarithromycin and combinations of two or more thereof. In some embodiments, the antibiotic is amoxicillin. In some embodiments, the antibiotic is clarithromycin. In some embodiments, the additional agent is an acid suppressor. In some embodiments, the additional agent is an acid suppressor is omeprazole. In some embodiments, the additional agent is an acid suppressor is pantoprazole. In some embodiments, the additional agent is an anti-microbial agent. In some embodiments, the anti-microbial agent is niclosamide.

Also described herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound of Formula (II):

or pharmaceutically acceptable salt thereof, wherein:represents a single or a double bond as valency permits; R5is hydrogen or oxygen; R6is selected from the group consisting of hydrogen and substituted or unsubstituted C1-6alkyl, provided that, when R5is oxygen R6is oxygen as valency permits; Y is carbon or nitrogen; Z is oxygen or sulfur; R7is oxygen or nitrogen, wherein the nitrogen is substituted with —NHC(O)NH2, —NHC(O)C1-6alkyl, —C(O)OH, or —C(O)O-C1-6alkyl; and R8is hydrogen, substituted or unsubstituted C1-6alkyl, or —OH, wherein R7and R8can be taken together to form a substituted or unsubstistuted 5-membered heteroaryl.

In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is an antibiotic. In some embodiments, the additional therapeutic agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, and combinations of two or more thereof. In some embodiments, the additional therapeutic agent is an aminoglycoside antibiotic. In some embodiments, the additional therapeutic agent is gentamicin. In some embodiments, the additional therapeutic agent is cationic antimicrobial peptide (CAMP). In some embodiments, the cationic antimicrobial peptide is defensin 1. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered consecutively. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously.

Additionally described herein is a method of killing or inhibiting the growth of H pylori, the method comprising contactingH. pyloriwith an effective amount of a compound of Formula (III):

or pharmaceutically acceptable salt thereof, wherein:represents a single or a double bond as valency permits, wherein whenis a single bond the nitrogen is substituted with hydrogen; R9is 5-7 membered heteroaryl optionally substituted with —NO2, —NH2, or halogen whenis a double bond; and whenis a single bond, R9is oxo; and R10is hydrogen or C1-6alkenyl optionally substituted with substituted or unsubstituted aryl whenis a single bond.

In some embodiments, the compound of Formula (III) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is an antibiotic. In some embodiments, the additional therapeutic agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, and combinations of two or more thereof. In some embodiments, the additional therapeutic agent is an aminoglycoside antibiotic. In some embodiments, the additional therapeutic agent is gentamicin. In some embodiments, the additional therapeutic agent is cationic antimicrobial peptide (CAMP). In some embodiments, the cationic antimicrobial peptide is defensin 1. In some embodiments, the compound of Formula (III) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered consecutively. In some embodiments, the compound of Formula (III) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously.

Additionally described herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound of Formula (IV):

or pharmaceutically acceptable salt thereof, wherein: X′ is carbon or phosphorus; R11is each and independently selected from the group consisting of substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6alkoxy, —NHC1-6alkyl, —NHC6H5, and C1-6alkenyl, wherein the alkenyl is optionally substituted with substituted or unsubstituted 5-7 membered aryl; and t is 1 or 2, wherein t is 1 when X′ is carbon; and when X′ is phosphorous t is 2.

In some embodiments, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is administered to the subject in combination with at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is an antibiotic. In some embodiments, the additional therapeutic agent is an antibiotic selected from the group consisting of a quinolone, a β-lactam, a cephalosporin, a penicillin, a carbapenem, a lipopetide, an aminoglycoside, a glycopeptide, a macrolide, an ansamycin, a sulfonamide, and combinations of two or more thereof. In some embodiments, the additional therapeutic agent is an aminoglycoside antibiotic. In some embodiments, the additional therapeutic agent is gentamicin. In some embodiments, the additional therapeutic agent is cationic antimicrobial peptide (CAMP). In some embodiments, the cationic antimicrobial peptide is defensin 1. In some embodiments, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered consecutively. In some embodiments, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously.

Additionally provided herein is a method of killing or inhibiting the growth ofH. pylori,the method comprising contactingH. pyloriwith an effective amount of a compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

Additionally provided herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

Additionally provided herein is a method of killing or inhibiting the growth ofH. pylori,comprising contactingH. pyloriwith a composition comprising an effective amount of a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Table 1, or pharmaceutically acceptable salt thereof.

Additionally provided herein is a method of treating a gastrointestinal infection caused byH. pyloriin a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Table 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Multiple Drug Resistance

Compositions and methods useful for treating and/or inhibiting acquisition of a multiple drug resistance (MDR) bacteria are described herein. The composition and methods described herein can be used to treat a subject at risk for exposure to or infection with an MDR bacterium. In some embodiments, the MDR bacterium is MDRH. pylori.In some embodiments, the MDR bacterium isH. pylori.Exemplary compositions and methods generally include use of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), including administering to a subject a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or a composition comprising a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to a subject having a multiple drug resistance (MDR) bacteria or at risk of having a multiple drug resistance (MDR) bacteria. Susceptibility and resistance to anti-bacterials are expressed as either a concentration or a zone diamter for growth inhibition. Clinical anti-bacterial “breakpoints” refer to the minimum inhibitory concentration (MIC) for a given anti-bacterial where there is a high likelihood of treatment failure, and are derived from human clinical studies or from knowledge derived from phamacodynamic and pharmacokinetic techniques applied to animal models. A large number of national societies and organizations set these break-points using various standards, and include the Clinical and Laboratory Standards Institute (CLSI) and the Food and Drug Administraion (FDA) in the US, the Swedeish Reference Group for Antibiotics (SRGA), the Japanese Society for Chemotherapy (JSC) etc. [see John Turnidge and David Paterson, Clinical Microbiology Reviews Vol 20 (3), July 2007 pp. 391-408].

Bacteria can employ several mechanisms in attaining MDR, e.g., modification of specific targeted enzyme so it is no longer inactivated by the drug, enzymatic deactivation of antibiotics, decreased cell wall permeability to antibiotic, altered target sites of antibiotic, efflux mechanisms to remove antibiotics, etc. Increased mutation rate as a stress response is a common mechanism for variants in altered sites aned enzymes to arise. Nearly all bacteria, e.g.,Staphylococci, Enterococci, Gonococci, Streptococci, Salmonella, Mycobacterium tuberculosis, Acinetobacterare able to exhibit MDR. Most bacteria, excludingMycobacteria,have multiple routes for acquiring and disseminating resistance to a drug. Resistance is spread clonally as bacteria grow. Plasmids can be transferred by conjugation to other bacteria, such as within the Enterobacteriaecae (E. Coli, EnterobacterandCitrobacterspecies). Transposition of the resistance gene to other plasmids also increases the ability of the resistant gene to be transferred between different bacteria.

A variety of other pathogens have emerged as multi drug resistant.Klebsiella pneumoniaecan cause nosocomial wound infections and is resistant to ampicillin. Many strains have acquired resistance to carbenicillin, quinolones, and increasingly to ceftazidime. The bacteria remain largely susceptible to aminoglycosides and cephalosporins. Cutaneous infection fromLeishmaniamajor generally results in chronic, painless skin lesions.Leishmania tropicaandLeishmania infantum-donovanimay be associated with visceralization and more chronic, reactivating illness. While treatment controls the clinical disease, it does not destroy the organism.

Mechanisms of Resistance

Four common mechanisms by which microorganisms exhibit resistance to antimicrobials are:

1. Drug inactivation or modification: e.g. enzymatic deactivation of beta-lactams in some Penicillin-resistant bacteria occurs through the production of β-lactamases which destroy the active part of the lactam. Vancoymycin resistance is typically the enzymatic removal of the last two peptides of the chain reducting its activity ˜1000 times.

2. Alteration of drug target site: The bacterium produces a modified protein or enzyme that binds to the drug, rendering it ineffective. For example, penicillin-binding proteins (PBP's) bind to beta-lactam antibiotics blocking their inhibition of cell wall construction. The drug can no longer act at the intended site.

3. Alteration of metabolic pathway: The bacteria utilize alternative pathways that bypass the metabolic pathway that the drug affects. For example, sulfanamides inhibit the synthesis of folic acid early in the bacterial metabolic pathway. Some sulfonamide-resistant bacteria, like mammalian cells, turn to utilizing preformed folic acid from a different pathway that is not affected by the sulfanamide.

4. Efflux pumps: Bacteria reduce drug accumulation by increasing active efflux (pumping out) of the drugs across the cell surface. The resistant bacteria can also reduce drug accumulation by decreasing drug permeability into the cell and/or its interaction once inside. (Efflux pumps are common mechanisms for ciprofloxacin and silver)

In some embodiments, a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or composition thereof can prevent or overcome one or more of these mechanisms described above (e.g., when administered to a subject having a bacterial infection or contacting a bacteria).

Mechanisms of Antibacterial Agents

Compositions and methods using a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) can be used to treat bacterial infection and/or inhibit the growth of bacteria.

Antibacterial action generally falls within one of four mechanisms, three of which involve the inhibition or regulation of enzymes involved in cell wall biosynthesis, nucleic acid metabolism and repair, or protein synthesis. The fourth mechanism involves the disruption of membrane structure, like a pore-former. A common example of a pore-former is polymixin B.

Many of these cellular functions targeted by antibiotics are most active in multiplying cells. Such cells are often rapidly dividing as are cancer cells and some antibacterials have also been found to be useful as anticancer agents.

Some antibacterials inhibit an enzyme necessary for bacterial survival or replication or block an enzymes binding site without contacting the enzyme specifically. These typically are found to interfere with cell wall synthesis, interfere with DNA synthesis, or interfere with protein synthesis. The latter mechanisms are disruption of a cell membrane, causing leakage, disruption of osmotic gradients, and loss of critical cellular contents.

Combination Therapies

In some embodiments, a composition of the present application further comprises one or more additional agents. The additional agent may be selected from any compound or agent known to have or that demonstrates advantageous properties when administered with a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating a subject in need thereof as disclosed herein comprises administering to the subject one or more additional agents. In some embodiments, a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof, can be used in combination with an antibiotic. In some embodiments, a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof, can be used in combination with an acid suppressor.

In some embodiments, the antibiotic is selected from the β-lactam class of antibiotic compounds.

In some embodiments, the antibiotic is selected from the cephalosporin class of antibiotic compounds. In some aspects of these embodiments, the antibiotic is selected from the group consisting of cefazolin, cefuroxime, ceftazidime, cephalexin, cephaloridine, cefamandole, cefsulodin, cefonicid, cefoperazine, cefoprozil, and ceftriaxone.

In some embodiments, the antibiotic is selected from the carbapenem class of antibiotic compounds. In some aspects of these embodiments, the antibiotic is selected from the group consisting of thienamycin, tomopenem, lenapenem, tebipenem, razupenem, imipenem, meropenem, ertapenem, doripenem, panipenem (betamipron), and biapenem.

In some embodiments, the antibiotic is selected from the lipopeptide class of antibiotic compounds. In some aspects of these embodiments, the antibiotic is selected from the group consisting of polymyxin B, colistin (polymyxin E), and daptomycin.

In some embodiments, the antibiotic is selected from the aminoglycoside class of antibiotic compounds. In some aspects of these embodiments, the antibiotic is selected from the group consisting of gentamicin, amikacin, tobramycin, debekacin, kanamycin, neomycin, netilmicin, paromomycin, sisomycin, spectinomycin, and streptomycin.

In some embodiments, the antibiotic is selected from the glycopeptide class of antibiotic compounds. In some aspects of these embodiments, the antibiotic is selected from the group consisting of vancomycin, teicoplanin, telavancin, ramoplanin, daptomycin, decaplanin, and bleomycin.

In some embodiments, the antibiotic is selected from the ansamycin class of antibiotic compounds. In some aspects of these embodiments, the antibiotic is selected from the group consisting of streptovaricin, geldanamycin, herbimycin, rifamycin, rifampin, rifabutin, rifapentine and rifamixin.

In some embodiments, the antibiotic is selected from the sulfonamide class of antibiotic compounds. In some aspects of these embodiments, the antibiotic is selected from the group consisting of sulfanilamide, sulfacetamide, sulfapyridine, sulfathiazole, sulfadiazine, sulfamerazine, sulfadimidine, sulfasomidine, sulfasalazine, mafenide, sulfamethoxazole, sulfamethoxypyridazine, sulfadimethoxine, sulfasymazine, sulfadoxine, sulfametopyrazine, sulfaguanidine, succinylsulfathiazole and phthalylsulfathiazole.

In some embodiments, the antibiotic is selected from the group consisting of quinolones, fluoroquinolones, β-lactams, cephalosporins, penicillins, carbapenems, lipopeptide antibiotics, glycopeptides, macrolides, ansamycins, sulfonamides, and combinations of two or more thereof.

In some embodiments, a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof, can be used in combination with an antifungal.

In some embodiments, the antifungal is selected from the polyene class of antifungal compounds. In some aspects of these embodiments, the antifungal is selected from the group consisting from Amphotericin B, Candicidin, Filipin, Hamycin, Natamycin, Nystatin, and Rimocidin.

In some embodiments, the antifungal is selected from the imidazole class of antifungal compounds. In some aspects of these embodiments, the antifungal is selected from the group consisting of Butoconazole, Clotrimazole, Econazole, Fenticonazole, Isoconazole, Ketoconazole, Luliconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, and Tioconazole.

In some embodiments, the antifungal is selected from triazole class of antifungal compounds. In some aspects of these embodiments, the antifungal is selected from the group consisting of Albaconazole, Efinaconazole, Epoxiconazole, Fluconazole, Isavuconazole, Itraconazole, Posaconazole, Propiconazole, Ravuconazole, Terconazole, and Voriconazole.

In some embodiments, the antifungal is selected from thiazole class of antifungal compounds. In some aspects of these embodiments, the antifungal is Abafungin.

In some embodiments, the antifungal is selected from Allylamine class of antifungal compounds.

In some embodiments, the antifungal is selected from Echinocandin class of antifungal compounds. In some aspects of these embodiments, the antifungal is selected from the group consisting of anidulafungin, caspofungin, and micafungin.

In some embodiments, the antifungal is selected from the group consisting of a polyene, an imidazole, a triazole, a thiazole, an allylamine, a thiocarbamate, an echinocandin, and combinations of two or more thereof

In some embodiments, the antifungal is fluconazole.

In some embodiments, the present application provides separate dosage forms of a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof and one or more of any of the above-described second agents, wherein the compound and second agent are associated with one another. The term “associated with one another” as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).

In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising:

(i) a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof ,

(ii) at least one additional agent (e.g., any one of agents described herein, for example aminoglycoside antibiotic such as gentamicin and cationic antimicrobial peptide such as defensin 1), and

(iii) a pharmaceutically acceptable carrier as described herein.

In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising:

(i) a compound described herein, e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof:

(ii) at least one additional agent (e.g., an antifungal such as a polyene, an imidazole, a triazole, a thiazole, an allylamine, a thiocarbamate, or echinocandin; e.g., antifungal is amphotericin B or fluconazole), and

(iii) a pharmaceutically acceptable carrier as described herein.

Some of the second agents referenced above will act synergistically with the compounds of the present application. In some embodiments, some of the second agents referenced above will show additive effect. When this occurs, it will allow the effective dosage of the second agent and/or the compound of the present application to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the second agent of a compound of the present application, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation.

Methods of Administration

The compounds and compositions described herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof or a composition comprising a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof) can be administered to a subject in a variety of ways. Exemplary methods of administration are described herein.

The compounds and compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. The methods and compositions of the described invention may be used in the form of drops or sprays (e.g., a nasal spray, aerosol spray, or pump spray) or other vehicles for inhalation or nasal administration (intranasal delivery). Aerosol spray preparations can be contained in a pressurized container with a suitable propellant such as a hydrocarbon propellant. Pump spray dispensers can dispense a metered dose or a dose having a specific particle or droplet size. Any dispensing device can be arranged to dispense only a single dose, or a multiplicity of doses. More generally, compositions of the invention formulated for inhalation or intranasal administration, can also be provided as solutions, suspensions, or viscous compositions. In some embodiments, the compositions of the invention (e.g., compositions of compounds described herein), are provided as solution compositions. In some embodiments, the compositions of the described invention can be delivered by other instruments, e.g., including but not limited to, a nebulizer, an insufflators, an inhaler, or a puffer.

The compounds and compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The compounds and compositions of this invention may also be administered rectally, for example in the form of suppositories or enema for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

When the compounds and compositions described herein can include one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

The compounds and compositions described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.02 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the compounds and compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.

Such administration can be used as a chronic or acute therapy. In some embodiments, a compound or composition described herein can be administered in a single dose per day. In some embodiments, a compound or composition described herein can be administered in a single dose per day. In some embodiments, a compound or composition described herein can be administered in a multiple doses per day. In some embodiments, a compound or composition described herein can be administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, a compound or composition described herein can be administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. In some embodiments, a compound or composition described herein can be administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 months. In some embodiments, administration can occur 1, 2, or 3 days after clearance of an infection. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.

A compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or composition described herein (e.g., a composition comprising a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof) can be provided in a kit. The kit includes (a) a composition that includes a compound described herein, and, optionally (b) informational material. The informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the compound described herein for the methods described herein.

The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to use of the compound described herein to treat a disorder described herein.

In one embodiment, the informational material can include instructions to administer the compound described herein in a suitable manner to perform the methods described herein, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein). Preferred doses, dosage forms, or modes of administration are parenteral, e.g., intravenous, intramuscular, subcutaneous, intraparenteral, bucosal, sublingual, intraoccular, and topical. In another embodiment, the informational material can include instructions to administer the compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein. For example, the material can include instructions to administer the compound described herein to such a subject.

The informational material of the kits is not limited in its form. In many cases, the informational material, e.g., instructions, is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet. However, the informational material can also be provided in other formats, such as computer readable material, video recording, or audio recording. In another embodiment, the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about a compound described herein and/or its use in the methods described herein. Of course, the informational material can also be provided in any combination of formats.

In addition to a compound described herein such as the compound of Fomula (I) as defined herein, the composition of the kit can include other ingredients, such as a solvent or buffer, a stabilizer, a preservative, and/or a second compound for treating a condition or disorder described herein. Alternatively, the other ingredients can be included in the kit, but in different compositions or containers than the compound described herein. In such embodiments, the kit can include instructions for admixing the compound described herein and the other ingredients, or for using a compound described herein together with the other ingredients.

The compound described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that the compound described herein be substantially pure and/or sterile. When the compound described herein is provided in a liquid solution, the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred. When the compound described herein is provided as a dried form, reconstitution generally is by the addition of a suitable solvent. The solvent, e.g., sterile water or buffer, can optionally be provided in the kit.

The kit can include one or more containers for the composition containing the compound described herein. In some embodiments, the kit contains separate containers, dividers or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label. In some embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of a compound described herein. For example, the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of a compound described herein. The containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.

The kit optionally includes a device suitable for administration of the composition, e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device. In a preferred embodiment, the device is an implantable delivery device.

Pharmaceutical Compositions

The compounds described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) can be formulated in a variety of manners, including for oral, or topical delivery (e.g., administered orally, parenterally, by inhalation spray, nebulizer, topically, rectally, nasally, buccally). Inclusion in feed, water or an inhaled formulation is particularly desirable for use with animals.

The compounds described herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof) can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.001 to about 100 mg/kg of body weight, e.g., between 0.001-1mg/kg, 1-100 mg/kg, or 0.01-5mg/kg, every 4 to 120 hours, e.g., about every 6, 8, 12, 24, 48, or 72 hours, or according to the requirements of the particular compound. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day. Alternatively, the compounds can be administered as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

Pharmaceutical compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; an additional compound including for example, a steroid or an analgesic; and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternate compositions of this invention comprise a compound described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. The compositions delineated herein include the compounds described herein, as well as additional therapeutic compounds if present, in amounts effective for achieving a modulation of disease or disease symptoms.

The compositions are generally made by methods including the steps of combining a compound described herein with one or more carriers and, optionally, one or more additional therapeutic compounds delineated herein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase which can be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The compounds of this invention may be administered by aerosol, nebulizer, or inhalation. In some embodiments, the composition is in the form of a dry powder, a suspension, or a solution. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Exemplary methods and devices for aerosol or inhalation include those described in U.S. Pat. No. 6,962,151, which is incorporated herein by reference in its entirety.

Compositions formulated for inhaled delivery generally include particles having a mean diameter of from about 0.1 μm to about 50 μm (e.g., from about 0.1 μm to about 10 μm, or from about 0.2 μm to about 5 μm. In some embodiments, the composition includes a dispersion of suitably-sized dry particles, for example, precipitants or crystals) or a dispersion of a solution (e.g., droplets) of a suitable size.

In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

When the compositions of this invention comprise a combination of compounds described herein, both the compounds are generally present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. Additionally, combinations of a plurality of compounds described herein are also envisioned. The compounds may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those compounds may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

Chemical Definitions

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

“Alkyl” refers to a radical of a straight—chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10alkyl (e.g., —CH3). In certain embodiments, the alkyl group is substituted C1-10alkyl. Common alkyl abbreviations include Me (—CH3), Et (—CH2CH3), iPr (—CH(CH3)2), nPr (—CH2CH2CH3), n-Bu (—CH2CH2CH2CH3), or i-Bu (—CH2CH(CH3)2).

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” and “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.

“Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH2CH2CH2—), butylene (—CH2CH2CH2CH2—), pentylene (—CH2CH2CH2CH2CH2—), hexylene (—CH2CH2CH2CH2CH2CH2—), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (—CH(CH3)—, (—C(CH3)2—), substituted ethylene (—CH(CH3)CH2—,—CH2CH(CH3)—, —C(CH3)2CH2—,—CH2C(CH3)2—), substituted propylene (—CH(CH3)CH2CH2—, —CH2CH(CH3)CH2—, —CH2CH2CH(CH3)—, —C(CH3)2CH2CH2—, —CH2C(CH3)2CH2—, —CH2CH2C(CH3)2—), and the like.

“Alkenyl” refers to a radical of a straight—chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon—carbon double bonds (e.g., 1, 2, 3, or 4 carbon—carbon double bonds), and optionally one or more carbon—carbon triple bonds (e.g., 1, 2, 3, or 4 carbon—carbon triple bonds) (“C2-20alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is substituted C2-10alkenyl.

“Alkenylene” refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (—CH═CH—) and propenylene (e.g., —CH═CHCH2—, —CH2—CH═CH—). Exemplary substituted alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (—C(CH3)═CH—, —CH═C(CH3)—), substituted propylene (e.g., —C(CH3)═CHCH2—, —CH═C(CH3)CH2—, —CH═CHCH(CH3)—, —CH═CHC(CH3)2—, —CH(CH3)—CH═CH—,—C(CH3)2—CH═CH—, —CH2—C(CH3)=CH—, —CH2—CH═C(CH3)—), and the like.

“Alkynylene” refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10alkyl.

The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-4alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and for 1 or 2 heteroatoms (“heteroC2-4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2-3alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

As used herein, “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to a divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14aryl. In certain embodiments, the aryl group is substituted C6-14aryl.

In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C1-8alkyl, C1-8haloalkyl, cyano, hydroxy, C1-8alkoxy, and amino.

Examples of representative substituted aryls include the following

Other representative aryl groups having a fused heterocyclyl group include the following:

wherein each W is selected from C(R66)2, NR66, O, and S; and each Y is selected from carbonyl, NR66, O and S; and R66is independently hydrogen, C1-8alkyl, C3-10cycloalkyl, 4-10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

Examples of representative heteroaryls include the following:

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

Particular examples of heterocyclyl groups are shown in the following illustrative examples:

“Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

“Amino” refers to the radical —NH2.

“Substituted amino” refers to an amino group of the formula —N(R38)2wherein R38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R38is not a hydrogen. In certain embodiments, each R38is independently selected from hydrogen, C1-8alkyl, C3-8alkenyl, C3-8alkynyl, C6-10aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl; or C1-8alkyl, substituted with halo or hydroxy; C3-8alkenyl, substituted with halo or hydroxy; C3-8alkynyl, substituted with halo or hydroxy, or —(CH2)t(C6-10aryl), —(CH2)t(5-10 membered heteroaryl), —(CH2)t(C3-10cycloalkyl), or —(CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-4alkyl, halo, unsubstituted C1-4alkoxy, unsubstituted C1-4haloalkyl, unsubstituted C1-4hydroxyalkyl, or unsubstituted C1-4haloalkoxy or hydroxy; or both R38groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to, —NR39—C1-8alkyl, —NR39—(CH2)t(C6-10aryl), —NR39—(CH2)t(5-10 membered heteroaryl), —NR39—(CH2)t(CH3-10cycloalkyl), and —NR39—(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39independently represents H or C1-8alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-4alkyl, halo, unsubstituted C1-4alkoxy, unsubstituted C1-4haloalkyl, unsubstituted C1-4hydroxyalkyl, or unsubstituted C1-4haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

“Azido” refers to the radical —N3.

“Carbamoyl” or “amido” refers to the radical —C(O)NH2.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO2.

“Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

“Heterocyclylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

“Cycloalkenyl” refers to substituted or unsubstituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

“Fused cycloalkenyl” refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Thioketo” refers to the group ═S.

These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle—aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

Disease, disorder, and condition are used interchangeably herein. In some embodiments, the disease is an infection caused by a bacterium.

In an embodiment, the methods provided herein can be used to treat an nosocomial infection caused byH. pylori.As used herein, a “nosocomial infection” refers to an infection which is a result of treatment in a hospital or a healthcare service unit, but secondary to the patient's original condition. Infections are considered nosocomial if they first appear 48 hours or more after hospital admission or within 30 days after discharge. This type of infection is also known as a hospital-acquired infection (or more generically a healthcare-associated infections).

In an embodiment, the methods provided herein can be used to treat a community-acquired infection caused byH. pylori.As used herein, a “community-acquired infection” refers also to an infection which is a result of activity in a highly populated facility or area. Any infection acquired in the community, that is, contrasted with those acquired in a health care facility (i.e., a nosocomial infection). An infection would be classified as community-acquired if the patient had not recently been in a health care facility or been in contact with someone who had been recently in a health care facility.

In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

As used herein, the term “treat” or “treatment” is defined as the application or administration of a compound to a subject, e.g., a patient, or application or administration of the compound to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a bacterial infection (e.g., a bacterial described herein) or a bacterial infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the bacterial infection, one or more symptoms of the bacterial infection or the predisposition toward the bacterial infection (e.g., to prevent at least one symptom of the bacterial infection or to delay onset of at least one symptom of the bacterial infection).

As used herein, an amount of a compound effective to treat a disorder, or a “therapeutically effective amount” refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.

As used herein, an amount of a compound effective to prevent a bacterial infection, or a “a prophylactically effective amount” of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in preventing or delaying the occurrence of the onset or recurrence of a disorder or a symptom of the bacterial infection.

As used herein, a “minimum inhibitory concentration (MIC)” is the lowest concentration of an anti-bacterial that inhibits the visible growth of a bacterium after overnight incubation. MIC can be used to confirm resistance of bacteria to an anti-bacterial agent and also to monitor the activity of new anti-bacterial agents. MIC can be determined by agar or broth dilution methods usually following the guidelines of a reference body such as the Clinical and Laboratory Standards Institute (CLSI), British Society for Antimicrobial Chemotherapy (BSAC) or The European Committee on Antimicrobial Susceptibility Testing (EUCAST). Methods to determine MIC are described, e.g., in Andrews J M.Journal of Antimicrobial Chemotherapy48 (Suppl. 1):5-16, (2001).

As used herein, “multiple drug resistance (MDR)” (also called multidrug resistance) is a condition enabling a disease-causing organism, e.g., bacteria, to no longer be killed or inhibited in growth by distinct drugs or chemicals, e.g., anti-bacterial agents in doses that are considered clinically relevent. A bacterium exhibiting MDR may also be referred to herein as a “multidrug-resistant” bacterium.

As used herein, “resistant microorganism or bacterium” means an organism which has become resistant to an anti-bacterial agent. In embodiments the minimum inhibitory concentration of a resistant bacterium will be at least, 2, 5, 10, or 100 greater than for that seen with a non-resistant bacterium for a selected anti-bacterial agent.

As used herein, “resistance breakpoint” is the threshhold concentration of an antibacterial agent above which a bacterium is considered resistant as defined above.

EXAMPLES

In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope.AbbreviationsACN: acetonitrileAGS: gastric adenocarcinoma cell linesCHO: chinese hamster ovary cellsCFU: colony-forming unitDCM: dichloromethane (also known as methylene chloride)DMEM: dulbecco's modified eagle mediumDMSO: dimethyl sulfoxideEC50: the concentration of a drug that gives half-maximal responseEDAC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideEtOAc: ethyl acetateFBS: fetal bovine serumFICI: fractional inhibitory concentration indexHCl: hydrochloric acidHOBT: hydroxybenzotriazoleHPLC-DAD-MS: high performance liquid chromatography with diode array detector coupled with mass spectrometryOD600: Optical density measured at a wavelength of 600 nmMeOH: methanolMgSO4: magnesium sulfateMHB: mycorrhiza helper bacteriaMIC: minimum inhibitory concentrationMLC: minimum lethal concentrationMBC: minimum bactericidal concentration. Also called minimum lethal concentration (MLC).mp: Melting pointMOI: multiplicity of infectionNMR: nuclear magnetic resonance spectroscopyNUAG: neutralizer agarPBS: phosphate-buffered salinePPI: proton pump inhibitorsRT: room temperatureTEA: trimethylamineTHF: tetrahydrofuranWST-1: 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium ZOI: zone of inhibition

Preparation of Exemplary Compounds

Method A: A solution of Compound A1, Compound B1, Compound C1, Compound D1, or Compound E1 in dichloromethane (DCM) (1 mL/mmol) containing triethylamine (TEA) (1 equivalent) is added dropwise to an equimolar solution of ethyl dichlorophosphate in DCM stirred at RT. After ˜18 h, the reaction mixture is concentrated and the residue is treated with tetrahydrofuran (THF) (1 mL/mmol), then vacuum filtered to remove TEA HCl. The filtrate is added dropwise to a mixture of hydrazine hydrate (4 equivalents) in an equal volume of THF stirred at 0° C. Stirring is continued overnight at room temperature, after which the lower phase of the reaction mixture is discarded, and the THF solution is concentrated. The crude hydrazide product (Compound A2, Compound B2, Compound C2, Compound D2, or Compound E2) is triturated with ether, washed with water, as necessary, and used directly in the next step without further purification.

Method B: A solution of Compound A1, Compound B1, Compound C1, Compound D1, or Compound E1 (2 equivalents) in THF (0.5 mL/mmol) is added dropwise to solution of ethyl dichlorophosphate (1 equivalent) in THF (1 mL/mmol) stirred at RT. After ˜18 h, the reaction mixture is vacuum filtered and the filter cake is washed with small portions of THF until washes are colorless. The filtrate is treated with hydrazine hydrate (4 equivalents) in one portion and the mixture is stirred for ˜18 h. The lower phase of the reaction mixture is discarded, and the THF solution is concentrated. The crude hydrazide product (Compound A2, Compound B2, Compound C2, Compound D2, or Compound E2) is triturated with ether, washed with water, as necessary, and used directly in the next step without further purification.

A mixture of hydrazide and equimolar 5-nitro-2-furaldehyde in MeOH (5 mL/mmol hydrazide) is stirred at reflux for 3 h. Solvent is removed under reduced pressure and the crude hydrazone is crystallized from a suitable solvent as described below (see “Methods of purification and characterization data for Compounds 1-5”).

Methods of Purification and Characterization Data for Compound 1, Compound 2, Compound 3, Compound 4, and Compound 5

Synthesis of Compound 13

A solution of 1,3-cyclohexanedione (A-3; 22.4 g, 200 mmol) in water (230 mL; Note 1) was added dropwise to a mixture of chloroacetaldehyde (40 mL, 40% in water, d 1.214, 247 mmol) in water (160 mL) containing sodium bicarbonate (20 g, 238 mmol) stirred at 0° C. After stirring 70 h at RT, the mixture was diluted with EtOAc (200 mL) and pH was adjusted to ˜1 with conc sulfuric acid. After 1 hour, the aqueous phase was extracted with EtOAc and the combined extracts were dried (MgSO4), filtered and concentrated to a syrup, which was purified by flash chromatography [hexane/EtOAc (4:1)] to accord A-4 as a solid (60% yield).

6,7-Dihydro-5H-benzofuran-4-one (A-4) was nitrated using conc sulfuric acid (I mL/mmol substrate) and sodium nitrate (1 equivalent). The reaction mixture was poured over ice, and the crude product was isolated by vacuum filtration and crystallized from boiling water to give pure 2-nitro-6,7-dihydro-5H-benzofuran-4-one (A-5).

An equimolar mixture of semicarbazide HCl and 2-nitro-6,7-dihydro-5-benzofuran-4-one (A-5) in 95% of ethanol (12 mL/mmol) was heated at 80° C. for 1 hour. The precipitates from the cooled reaction mixture were filtered to give compound 13 as a solid (95%).

Synthesis of Compound 15

An equimolar mixture of 2-nitro-6,7-dihydro-S5H-benzofuran-4-one (A-5) and A-2 in methanol (3 mL/mmol) was heated at 70° C. for 3 hours. The reaction mixture was concentrated, and the residue was titurated with water. The crude product was purified by flash chromatography to give compound 15 as a solid.

Synthesis of Compound 16

A mixture of cinnamic acid (A-6) in ACN (2 mL/mmol) stirred at room temperature was treated with HOBT (1.2 equivalents), followed by EDAC HCl (1.2 equivalents). After stirring for 2.5 h, the mixture was added dropwise to a solution of hydrazine hydrate (2 equivalents) in an equal volume of ACN stirred at 0° C. After warming to 10° C., the reaction mixture was diluted with water and extracted with EtOAc. EtOAc extracts were washed with saturated sodium bicarbonate solution and concentrated to give cinnamic acid hydrazide (A-7) of adequate purity to be used in the next step.

An equimolar mixture of A-7 and 2-nitro-6,7-dihydro-5H-benzofuran-4-one (A-5) in methanol (5 mL/mmol) was heated at 70° C. for 3 hours. The reaction mixture was concentrated and the residue was titurated with water. The precipitates from the cooled reaction mixture were filtered to give compound 16 as a solid.

Preparation of Exemplary Compounds

Synthesis of Additional Compounds

Synthesis of Compound 17

A solution of 100 in ether was added dropwise to a mixture of POCl3in ether stirred at 0° C. After stirring overnight at ambient temperature, the reaction mixture was vacuum filtered, and the filtrate was concentrated to an orange-colored solid (101) that was used directly in the next step without further purification.

A solution of morpholine and DIPEA in ether was added dropwise to a solution of 12 in ether stirred at 0° C. After stirring overnight at ambient temperature, the solvent was decanted from a residual solid and concentrated to a lightly colored solid (103) that was used directly in the next step without further purification.

A solution of 103 in THF was added dropwise to a mixture of hydrazine hydrate in THF stirred at 0° C. After stirring overnight at ambient temperature, the reaction mixture was vacuum filtered, and the filtrate was concentrated to a syrup that was partitioned between EtOAc-water. The organic phase was washed with water, and the combined aqueous phases were concentrated to dryness, sonicated with THF, and vacuum filtered (Celite). The filtrate was concentrated to a syrup that was taken up in EtOAc, treated with MgSO4and activated charcoal, vacuum filtered (Celite) and concentrated to a hard, yellow foam (104).

A mixture of 104 and 2-nitro-6,7-dihydro-5H-benzofuran-4-one (A-5) in EtOH was stirred at reflux for ˜4 h. After cooling to RT, the reaction mixture was vacuum filtered, and the filtrate was concentrated to a semi-solid that was triturated with ether, dried, sonicated with a large volume of water, collected by vacuum filtration, washed with water and air-dried. The pure compound [17; >98% [UHPLC (210 nm)]; m/z 434.16425 (M+H)+] was obtained by crystallization from 2-BuOH.

A mixture of substituted cinnamic acid in ACN stirred at room temperature was treated with HOBT (1.2 equivalents), followed by EDAC (1.2 equivalents). After stirring for 4-5 h, the mixture was added dropwise to a mixture of hydrazine hydrate (10 equivalents) in ACN stirred at 0° C. The reaction mixture was stored in the freezer overnight. The solvents were decanted, and the residual solid was sonicated with saturated NaHCO3, collected by vacuum filtration, washed with saturated NaHCO3, washed with water and air-dried. The hydrazide was pure enough to use directly in the next step.

An equimolar mixture of hydrazide from step 1) and 2-nitro-6,7-dihydro-5H-benzofuran-4-one (A-5) in methanol was heated at reflux for 3 hours. Upon cooling, the product precipitated from solution, was collected by vacuum filtration, washed with MeOH and air-dried:

Determination of MIC and MBC Concentration AgainstH. pylorifor Exemplary Compounds

The MIC and MBC of the compounds can be measured with the following procedure: In vitro antibacterial activity was tested using the broth microdilution assay. Experiments were carried out in triplicate using Müller-Hinton broth supplemented with 10% FBS in 96-well plates at a total assay volume of 100 μL. Antimicrobials were tested againstH. pylori.Two-fold serial dilutions were prepared between the concentration range 0.01-64 μg/mL. An initial bacterial inoculum was adjusted to OD600=0.06 and incubated with test compounds at 37° C. for 3 days in humidified incubators under the 5% CO2atmosphere. OD600was measured and the lowest concentration of compound that inhibited bacterial growth was reported as the MIC. See Gwisai T, et al. Repurposing niclosamide as a versatile antimicrobial surface coating against device-associated, hospital-acquired bacterial infections.Biomed Mater.2017;12(4):045010. The pH was adjusted to acidic condition with 1 N HCl. The minimal bactericidal concentration (MBC) was determined by plating 5 μL of broth culture from the MIC assay onto Müller-Hinton agar (BD Biosciences) supplemented with 10% FBS. After 72 h, the lowest concentration at which colonies were not observed was reported as the MBC.

MIC and MBC data for exemplary compounds based on the above MIC and MBC procedures are shown in Table 4.

TABLE 4MIC and MBC data for exemplary compounds againstH. pylori.CompoundMICMBCNo.(μg/mL)(μg/mL)11-22222322411511622722844944104411111211130.250.251444150.250.25160.250.25Niclosamide0.250.5Amoxicillin0.010.025

MIC with Different Strains

MIC data with different strains ofH. pyloriis shown in Table 5.

Synergy of Exemplary Compounds with Secondary Agent

Antibacterial synergy was tested using the checkerboard assay. The compound of interest was combined with antibiotics and proton pump inhibitors (PPIs). In this series of experiments cultures ofH. pyloriwere adjusted to OD600=0.06 and added to compound pairs that had been serially diluted in the same 96-well plates, vertically for one compound and horizontally for the other. Assays were carried out in triplicate as described in the antibacterial susceptibility assay sub-section. The combinatorial inhibitory concentration was indicated by the FICI:

According to EUCAST (2000) a Synergistic effect (SynE) is observed when FICI value is ≤0.5; an Additive effect (AddE) when 0.5<FICI value<1; an Indifferent effect (IndE) when 1<FICI value<2 and an Antagonistic effect (AntE) when FICI value>2.

MIC in Acidic pH Environments

MIC data in acidic pH is shown in Table 6 for selected compounds identified by compound number.

Amount of Time to KillH. pylori—Low Dose and High Dose ofH. pylori

The time taken to kill low dose ofH. pyloriwith using compounds 1, 13, 15, 16, and amoxacillin were measured. SeeFIG.2.

The time taken to kill high dose ofH. pyloriwith using compounds 1, 13, 15, 16, and amoxacillin were measured. SeeFIG.3.

The antibacterial properties of the compounds againstH. pyloriwere examined using killing kinetic assays. Briefly, agar grownH. pyloribacteria were suspended in fresh MHB with 10% FBS to a density of 109cells/mL and placed into 10 mL tubes (BD Biosciences). Test compounds were then added at the 4×MIC and incubated with agitation at 37° C. under microaerophilic conditions. Aliquots were periodically drawn from the tubes, serially diluted and plated onto Brucella agar (BD Biosciences) supplemented with 10% FBS. CFUs were counted after a 3-day incubation and assays were carried out in duplicate.

Motility Measurements

The motility of compounds 1, 13, 15, and 16 were measured as demonstrated byFIG.4.

In brief, Brucella agar with 10% FBS was prepared in 2 layers. The bottom layer contained pre-casted 1.5% agar and the softer top layer was comprised of 0.4% agar and the compound (75, 100, 150 or 200 ng/mL). Agar-grownH. pyloricells were sliced and the densely grownH. pyloriagar slice was placed facing up towards the soft layer and incubated as described in bacteria and mammalian cell culture subsection.

Cytotoxicity of different concentrations of compounds 1, 13, 15, and 16 in an MKN 28-gastric cell line was measured. SeeFIG.5.

Cytotoxicity of different concentrations of compounds 1, 13, 15, and 16 in an AGS-gastric cell line was measured. SeeFIG.6.

A procedure to measure the cytotoxicities is provided below:

HepG2 and AGS cells were used to test the cytotoxicity of the compounds. Cells were grown in DMEM (Gibco) supplemented with 10% fetal bovine serum (FBS) (Gibco) and 1% penicillin/streptomycin (Gibco) and maintained at 37 ° C. in 5% CO2. 5×104cells in 100 μL were added to wells of 96-well plates. Compounds were serially diluted in serum and antibiotic-free DMEM and added to the monolayer and incubated at 37° C. in 5% CO2for 24 h. At 4 h prior to the end of the incubation period, 10 μL of 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium (WST-1) solution (Roche, Mannheim, Germany) was added to each well. The WST-1 reduction was monitored at 450 nm using a Vmax microplate reader. Assays were performed in triplicate and the percentage survival was calculated by comparing the compound-treated wells to the DMSO-treated vehicle controls.

H. pyloriAdhesion to Gastric Epithelial Cells

H. pyloriadhesion to gastric epithelial cells were measured at different time points. SeeFIG.7. A procedure for measuring this adhesion is provided below:

The AGS (Gastric adenocarcinoma cell lines) cell line was used to examine inhibition of adhesion and invasion ofH. pyloriby the compound of interest. The AGS cells were grown in DMEM (Gibco), supplemented with 10% fetal bovine serum (FBS) (Gibco) and 1% penicillin/streptomycin (Gibco) and maintained at 37° C. in 5% CO2. Then, 5×105cells in antibiotic and serum-free DMEM were seeded in 6-well plates 24 h prior to infection.H. pyloribacteria at a multiplicity of infection (MOI)=100 were added and allowed to adhere to the surface of the AGS cells. Planktonic bacteria were removed after 2 h and DMEM with the compound (1×MIC) was then added to the wells containing the AGS. The mammalian cells were lysed by 0.1% saponin after 20 h of incubation and the adhered bacteria were then serially diluted, plated in Brucella agar supplemented with 10% FBS, and incubated as described earlier. To determine the bacterial invasion inhibition, AGS cells were treated with DMEM supplemented with 200 μ/mL gentamicin and incubated for 1.30 h to eliminate extracellular bacteria. Antibiotic and serum-free DMEM with and without test compounds were added and incubated in 5% CO2for 20 h. Cell lysate preparation, plating, and incubation were carried out as we described in the adhesion assay. Assays were carried out in triplicate.

Vacuolation inhibition of compounds 1, 13, 15, and 16 were measured againstH. pyloriand MKN. SeeFIGS.8and9. A procedure to measure vacuolation inhibition is provided below:

H. pyloribacteria secrete VacA toxin via a type V secretion system. This toxin binds to host gastric epithelial cells and its internalization leads to vacuolation, characterized by the accumulation of large vacuoles in gastric epithelial cells during the infection process. AGS cells were harvested and seeded into a 6 well plate at a concentration of 5×105cells, 24 h before experimentation.H. pyloribacteria were harvested and washed with sterile PBS and co-cultured with AGS at a MOI of 100. After incubation for 24 h, the cells were washed, magnified under a microscope, and examined for vacuolation.

Insect Survival

The percentage of insects surviving the treatment of compounds 1, 13, 15, and 16 at different time points were measured. SeeFIG.10. An exemplary procedure to assess insect survival is provided below:

Twelve randomly selectedG. mellonellalarvae 300-350 mg was used for each group in the experiment.H. pyloricells were washed with PBS and diluted to OD600=0.3, before inoculation intoG. mellonellalarvae. A 10 μL inoculum was injected into the last left proleg using a 10 μL Hamilton syringe. After 2 h, compounds were administered at into the last right proleg and the wax moths were incubated at 37° C. Three control groups—(1) injected with PBS only, (2) inoculated withH. pyloribut treated with sham injections, (3) no manipulation—were included.G. mellonellasurvival was evaluated up to 120 h and considered dead if unresponsive to touch. Killing curves and differences in survival were analyzed by the Kaplan-Meier method using GraphPad Prism version 6.04 (GraphPad Software, La Jolla, Calif., USA). Statistical analysis (Kruskal-Wallis test) was carried out using the same program.

OTHER EMBODIMENTS

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above

Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.