Bacterial efflux pump inhibitors for the treatment of ophthalmic and otic infections

1. A method of therapeutic treatment of a gram negative bacterial infection in an eye or ear of a subject, comprising co-administering to the eye or ear infected with a gram negative bacteria having an efflux pump an effective amount of an antimicrobial agent and a compound of formula I:

wherein R 1 and R 2 are separately selected from the group consisting of amine and C 1-4 alkylamine;

linkers L 1 and L 3 are separately selected from the group consisting of amine and C 1-2 alkylamine or are separately absent;

aromatic rings A 1 and A 2 are separately selected from the group consisting of

wherein Z 1 -Z 4 are each C, with the proviso that aromaticity of the aromatic rings are maintained;

Z 1 -Z 4 that are C are optionally substituted with C 1-4 alkyl, CH 2 NH 2 , halogen, methoxy, CH 2 C(O)NMe 2 , C(O)NH 2 , C(O)NMe 2 , SO 2 Me, or SO 2 NH 2 ;

linker L 2 is a 1 to 12 unit chain, wherein each units is independently selected from the group consisting of CH 2 , C(CH 3 ) 2 , O, C(O), S, S(O), S(O) 2 , NH, NR 4 , phenyl, monocyclic 5-membered heteroaryl, monocyclic 6-membered heteroaryl, —CH═CH— cis, —CH═CH— trans, NHC(O)NH, NR 4 C(O)NH, NHC(O)NR 4 , NR 4 C(O)NR 4 , OC(O)NH, NR 4 C(O)O, OC(O)NR 4 , and NHC(O)O with the proviso that L 2 does not contain a C(O)NH, C(O)NR 4 , C(O)O, or C(O)S unit;

wherein the 5-membered heteroaryls are selected from the group consisting of imidazole, furane, thiophene, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, and 1,3,4-triazole;

the 6-membered heteroaryls are selected from the group consisting of pyridine, pyrimidine, pyridazine, 1,2,4-triazine, and 1,3,5-triazine; and

R 4 is selected from the group consisting of H and C 1-4 alkyl.

2. The method of claim 1 , wherein the microbial infection is infection with one or more organisms selected from the group consisting of Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii , and Bacteroides splanchnicus.

3. The method of claim 1 , wherein the infection is one or more of otitis media, otitis externa, malignant otitis externa, and mastoiditis.

4. The method of claim 1 , wherein the infection is ophthalmic Pseudomonas aeruginosa.

5. The method of claim 1 , wherein the compound of formula I is selected from the group consisting of propamidine, pentamidine, hexamidine, dibromopropamidine,

6. The method of claim 1 , wherein the co-administration comprises administering a pharmaceutical composition that comprises both the compound of formula I and the antimicrobial agent to the eye or ear.

7. The method of claim 1 , wherein the co-administration comprises topically administering the compound of formula I and the antimicrobial agent to the eye or ear.

8. The method of claim 1 , wherein the co-administration comprises injecting the compound of formula I and the antimicrobial agent into the eye.

9. The method of claim 1 , wherein the compound of formula I and the antimicrobial agent are administered simultaneously.

10. The method of claim 1 , wherein the compound of formula I and the antimicrobial agent are administered sequentially.

11. A method for reducing the onset of a gram negative bacterial infection in an eye or ear of a subject, comprising co-administering to an eye or ear at risk of infection with a gram negative bacteria having an efflux pump an effective amount of an antimicrobial agent and a compound of formula I:

wherein R 1 and R 2 are separately selected from the group consisting of amine and C 1-4 alkylamine;

linkers L 1 and L 3 are separately selected from the group consisting of amine and C 1-2 alkylamine or are separately absent;

aromatic rings A 1 and A 2 are separately selected from the group consisting of

wherein Z 1 -Z 4 are each C, with the proviso that aromaticity of the aromatic rings are maintained;

Z 1 -Z 4 that are C are optionally substituted with C 1-4 alkyl, CH 2 NH 2 , halogen, methoxy, CH 2 C(O)NMe 2 , C(O)NH 2 , C(O)NMe 2 , SO 2 Me, or SO 2 NH 2 ;

linker L 2 is a 1 to 12 unit chain, wherein each unit is independently selected from the group consisting of CH 2 , C(CH 3 ) 2 , O, C(O), S, S(O), S(O) 2 , NH, NR 4 , ═N—, phenyl, monocyclic 5-membered heteroaryl, monocyclic 6-membered heteroaryl, —CH═CH— cis, —CH═CH— trans, NHC(O)NH, NR 4 C(O)NH, NHC(O)NR 4 , NR 4 C(O)NR 4 , OC(O)NH, NR 4 C(O)O, OC(O)NR 4 , and NHC(O)O with the proviso that L 2 does not contain a C(O)NH, C(O)NR 4 , C(O)O, or C(O)S unit;

wherein the 5-membered heteroaryls are selected from the group consisting of imidazole, furane, thiophene, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole, and 1,3,4-triazole;

the 6-membered heteroaryls are selected from the group consisting of pyridine, pyrimidine, pyridazine, 1,2,4-triazine, and 1,3,5-triazine; and

R 4 is selected from the group consisting of H and C 1-4 alkyl.

12. The method of claim 11 , wherein the compound of formula I is selected from the group consisting of propamidine, pentamidine, hexamidine, dibromopropamidine,

13. The method of claim 11 , wherein the co-administration comprises administering a pharmaceutical composition that comprises both the compound of formula I and the antimicrobial agent to the eye or ear.

14. The method of claim 11 , wherein the co-administration comprises topically administering the compound of formula I and the antimicrobial agent to the eye or ear.

15. The method of claim 11 , wherein the co-administration comprises injecting the compound of formula I and the antimicrobial agent into the eye.

16. The method of claim 11 , wherein the compound of formula I and the antimicrobial agent are administered simultaneously.

17. The method of claim 11 , wherein the compound of formula I and the antimicrobial agent are administered sequentially.