Claims
- 1. An inhibitor of an efflux pump for treating an infection caused by a microbe in a subject consisting of a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group, wherein said inhibitor inhibits efflux pump activity.
- 2. The inhibitor of claim 1, wherein said inhibitor is an aminoglycoside comprising at least two nitrogen atoms that are each bonded to a lipophilic group.
- 3. The inhibitor of claim 1, wherein said lipophilic group is a substituted or unsubstituted N-benzyl group.
- 4. The inhibitor of claim 3, wherein the phenyl group of the N-benzyl group is substituted with one to five groups selected from C1-C5 straight or branched alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, carbocyclic, aryl, aryloxy, aralkyl, aryloxyalkyl, arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heteroaryl group, (CR′R″)0-3NR′R″, (CR′R″)0-3CN, NO2, halogen, (CR′R″)0-3C(halogen)3, (CR′R″)0-3CH(halogen)2, (CR′R″)0-3CH2(halogen), (CR′R″)0-3CONR′R″, (CR′R″)0-3(CNH)NR′R″, (CR′R″)0-3S(O)1-2NR′R″, (CR′R″)0-3CHO, (CR′R″)0-3O(CR′R″)0-3H, (CR′R″)0-3S(O)0-3R′, (CR′R″)0-3O(CR′R″)0-3H, (CR′R″)0-3S(CR′R″)0-3H, (CR′R″)0-3OH, (CR′R″)0-3COR′, (CR′R″)0-3(substituted or unsubstituted phenyl), (CR′R″)0-3(C3-C8 cycloalkyl), (CR′R″)0-3CO2R′, and (CR′R″)0-3OR′ groups, wherein each of R′ and R″ is independently hydrogen or a C1-C5 alkyl group.
- 5. The inhibitor of claim 1, wherein said inhibitor has the following structure:
- 6. The inhibitor of claim 1, wherein said inhibitor has the following structure:
- 7. The inhibitor of claim 1, wherein said inhibitor has the following structure:
- 8. The inhibitor of claim 1, wherein said inhibitor has the following structure:
- 9. The inhibitor of claim 1, wherein said inhibitor has the following structure:
- 10. The inhibitor of claim 1, wherein said inhibitor has either of the following structures:
- 11. A method for treating a microbial infection in an animal, comprising administering to an animal suffering from said infection an efflux pump inhibitor in an amount sufficient to reduce efflux pump activity, wherein said inhibitor is a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group, such that infection is inhibited.
- 12. A method of treating an infection caused by a microbe in a subject comprising administering an inhibitor of an efflux pump to the subject such that the infection is treated, wherein said inhibitor is a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group, such that said infection is treated.
- 13. A method of enhancing the antimicrobial activity of an antimicrobial agent against a microbe, comprising contacting said microbe with said antimicrobial agent and an efflux pump inhibitor in an amount effective to inhibit an efflux pump in said microbe, wherein said inhibitor is a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group, such that said activity is enhanced.
- 14. The method of any of claims 11, 12, or 13, wherein said microbe is a bacterium.
- 15. The method of claim 14, wherein said bacterium sis elected 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, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saccharolyticus.
- 16. The method claim 14, wherein said antimicrobial agent is effluxed by a microbe.
- 17. The method of claim 14, wherein said microbe is a drug resistant microbe.
- 18. The method of claim 14, wherein said microbe is a highly drug resistant microbe.
- 19. The method of claim 14, wherein said microbe is highly resistant to an antibiotic.
- 20. The method of claim 19, wherein the microbial cell comprises at least one chromosomal mutation in a drug target gene.
- 21. The method of claim 20, wherein the mutation is present in a gene selected from the group consisting of gyrase, topoisomerase, and fabI.
- 22. The method of claim 14, wherein the inhibitor is an inhibitor of an efflux pump and is administered prophylacticly.
- 23. The method of claim 14, wherein the inhibitor is an inhibitor of an efflux pump and is administered therapeutically.
- 24. The method of claim 14, further comprising administering an antibiotic to the subject.
- 25. The method of claim 24, wherein the inhibitor and the antibiotic are administered as a pharmaceutical composition comprising the inhibitor, the antibiotic, and a pharmaceutically acceptable carrier.
- 26. The method of claim 25, wherein said drug is a peptide deformylase inhibitor.
- 27. A method of enhancing the antimicrobial activity of a drug comprising contacting a microbe that is resistant to one or more drugs with a drug to which the microbe is resistant and an inhibitor of an efflux pump to thereby enhance the antimicrobial activity of a drug, wherein said inhibitor is a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group, such that said antimicrobial activity is enhanced.
- 28. The method of claim 27, wherein the step of contacting occurs ex vivo.
- 29. A pharmaceutical composition effective for treatment of an infection of an animal by a microbe, comprising an efflux pump inhibitor and a pharmaceutically acceptable carrier, wherein said inhibitor is a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group.
- 30. A composition comprising a non-antibiotic bactericidal or bacteriostatic first agent and a second agent that inhibits the expression or activity of an efflux pump, wherein said inhibitor is a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group.
- 31. The composition of claim 30, wherein the first agent is an antibiotic.
- 32. The composition of claim 31, wherein the second agent is selected from the group consisting of N-benzylated polyazaalkanes, N-benzylated polyaminoalkanes, or mixed N-benzylated poly(aza/amino)alkanes, any carbon atom of which may be hydroxyl, amino, or oxo substituted.
- 33. The composition of claim 32, wherein the second agent inhibits an acr-like efflux pump.
- 34. A pharmaceutical composition comprising an antibiotic and an inhibitor of an efflux pump selected from the group consisting of N-benzylated polyazaalkanes, N-benzylated polyaminoalkanes, or mixed N-benzylated poly(aza/amino)alkanes, any carbon atom of which may be hydroxyl, amino, or oxo substituted.
- 35. The composition of claim 34, further comprising a pharmaceutically acceptable carrier.
- 36. The composition of claim 34, wherein the antibiotic is a peptide deformylase inhibitor.
- 37. The composition of claim 34, wherein the pharmaceutically acceptable carrier is an inhibitor of the pump.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application No. 60/438,754, “Substituted Polyamines as Inhibitors of Bacterial Efflux Pumps” filed on Jan. 8, 2003, U.S. Provisional Patent Application No. 60/438,653, “Substituted Polyamines as Inhibitors of Bacterial Efflux Pumps” filed on Jan. 8, 2003, and to U.S. Provisional Patent Application No 60/438,725, “Substituted Polyamines as Inhibitors of Bacterial Efflux Pumps” filed on Jan. 7, 2003. The entire contents of each of these patent applications are hereby incorporated herein by reference.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60438725 |
Jan 2003 |
US |
|
60438653 |
Jan 2003 |
US |
|
60438754 |
Jan 2003 |
US |