Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli

Antimicrobial Agents and Chemotherapy

Volumn 58, Issue 2, 2014, Pages 722-733

  Opperman, Timothy J ^a   Kwasny, Steven M ^a   Kim, Hong Suk ^b   Nguyen, Son T ^a   Houseweart, Chad ^a   D'Souza, Sanjay ^c   Walker, Graham C ^c   Peet, Norton P ^a   Nikaido, Hiroshi ^b   Bowlin, Terry L ^a  

^a MICROBIOTIX INC   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIAL PROTEIN; CEFOTAXIME; CIPROFLOXACIN; FLUORESCENT DYE; HOE 33342; LEVOFLOXACIN; MBX 2319; PIPERACILLIN; PROTEIN ACRAB; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANTIBACTERIAL ACTIVITY; ARTICLE; BACTERICIDAL ACTIVITY; ENTEROBACTERIACEAE; ESCHERICHIA COLI; GRAM NEGATIVE BACTERIUM; MINIMUM INHIBITORY CONCENTRATION; MULTIDRUG RESISTANCE; NONHUMAN; PRIORITY JOURNAL; PSEUDOMONAS AERUGINOSA;

ANTI-BACTERIAL AGENTS; BACTERIAL PROTEINS; CARRIER PROTEINS; CIPROFLOXACIN; DIPEPTIDES; DRUG RESISTANCE, MULTIPLE, BACTERIAL; DRUG SYNERGISM; ENTEROBACTERIACEAE; ESCHERICHIA COLI; ESCHERICHIA COLI PROTEINS; LEVOFLOXACIN; MEMBRANE TRANSPORT MODULATORS; MICROBIAL SENSITIVITY TESTS; PIPERACILLIN; PYRANS; PYRIDINES;

EID: 84893517787     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.01866-13     Document Type: Article

References (53)

1. Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC, Oh MD, Choe KW. 2005. Risk factors for antimicrobial resistance and influence of resistance on mortality in patients with bloodstream infection caused by Pseudomonas aeruginosa. Microb. Drug Resist. 11:68-74. http://dx.doi.org/10.1089/mdr.2005. 11.68.
2. Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC, Oh MD, Choe KW. 2005. Clinical epidemiology of ciprofloxacin resistance and its relationship to broad-spectrum cephalosporin resistance in bloodstream infections caused by Enterobacter species. Infect. Control Hosp. Epidemiol. 26:88-92. http://dx.doi.org/10.1086/502492.
3. Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC, Oh MD, Choe KW. 2005. Bloodstream infections caused by antibiotic-resistant Gramnegative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob. Agents Chemother. 49:760-766. http://dx.doi.org/10. 1128/AAC.49.2.760-766.2005.
4. Kibbey CE, Poole SK, Robinson B, Jackson JD, Durham D. 2001. An integrated process for measuring the physicochemical properties of drug candidates in a preclinical discovery environment. J. Pharm. Sci. 90:1164-1175. http://dx.doi.org/10.1002/jps.1070.
5. Peleg AY, Hooper DC. 2010. Hospital-acquired infections due to Gramnegative bacteria. N. Engl. J. Med. 362:1804-1813. http://dx.doi.org/10. 1056/NEJMra0904124.
6. Anthony KB, Fishman NO, Linkin DR, Gasink LB, Edelstein PH, Lautenbach E. 2008. Clinical and microbiological outcomes of serious infections with multidrug-resistant Gram-negative organisms treated with tigecycline. Clin. Infect. Dis. 46:567-570. http://dx.doi.org/10.1086/526775.
7. Nikaido H, Pages JM. 2012. Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol. Rev. 36:340-363. http://dx.doi.org/10.1111/j.1574-6976.2011.00290.x.
8. Nikaido H, Takatsuka Y. 2009. Mechanisms of RND multidrug efflux pumps. Biochim. Biophys. Acta 1794:769-781. http://dx.doi.org/10.1016/j.bbapap.2008.10. 004.
9. Piddock LJ. 2006. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin. Microbiol. Rev. 19:382-402. http://dx.doi.org/10.1128/CMR.19.2.382-402.2006.
10. Li XZ, Zhang L, Srikumar R, Poole K. 1998. Beta-lactamase inhibitors are substrates for the multidrug efflux pumps of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 42:399-403.
11. Nakae T, Saito K, Nakajima A. 2000. Effect of sulbactam on antipseudomonal activity of beta-lactam antibiotics in cells producing various levels of the MexAB-OprM efflux pump and beta-lactamase. Microbiol. Immunol. 44:997-1001. http://dx.doi.org/10.1111/j.1348-0421.2000.tb02595.x.
12. Yoshida K, Nakayama K, Ohtsuka M, Kuru N, Yokomizo Y, Sakamoto A, Takemura M, Hoshino K, Kanda H, Nitanai H, Namba K, Yoshida K, Imamura Y, Zhang JZ, Lee VJ, Watkins WJ. 2007. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate. Bioorg. Med. Chem. 15:7087-7097. http://dx.doi.org/10.1016/j.bmc.2007.07.039.
13. Lomovskaya O, Lee A, Hoshino K, Ishida H, Mistry A, Warren MS, Boyer E, Chamberland S, Lee VJ. 1999. Use of a genetic approach to evaluate the consequences of inhibition of efflux pumps in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 43:1340-1346.
14. Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R, Lee M, Blais J, Cho D, Chamberland S, Renau T, Leger R, Hecker S, Watkins W, Hoshino K, Ishida H, Lee VJ. 2001. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob. Agents Chemother. 45:105-116. http://dx.doi.org/10.1128/ AAC.45.1.105-116.2001.
15. Singh R, Swick MC, Ledesma KR, Yang Z, Hu M, Zechiedrich L, Tam VH. 2012. Temporal interplay between efflux pumps and target mutations in development of antibiotic resistance in Escherichia coli. Antimicrob. Agents Chemother. 56:1680-1685. http://dx.doi.org/10.1128/AAC.05693-11.
16. Nishino K, Latifi T, Groisman EA. 2006. Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium. Mol. Microbiol. 59:126-141. http://dx.doi.org/10.1111/j.1365-2958.2005.04940.x.
17. Kvist M, Hancock V, Klemm P. 2008. Inactivation of efflux pumps abolishes bacterial biofilm formation. Appl. Environ. Microbiol. 74:7376-7382. http://dx.doi.org/10.1128/AEM.01310-08.
18. Van Bambeke F, Pages JM, Lee VJ. 2006. Inhibitors of bacterial efflux pumps as adjuvants in antibiotic treatments and diagnostic tools for detection of resistance by efflux. Recent Pat. Antiinfect. Drug Discov. 1:157-175. http://dx.doi.org/10.2174/157489106777452692.
19. Renau TE, Leger R, Filonova L, Flamme EM, Wang M, Yen R, Madsen D, Griffith D, Chamberland S, Dudley MN, Lee VJ, Lomovskaya O, Watkins WJ, Ohta T, Nakayama K, Ishida Y. 2003. Conformationallyrestricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett. 13: 2755-2758. http://dx.doi.org/10.1016/ S0960-894X(03)00556-0.
20. Renau TE, Leger R, Flamme EM, Sangalang J, She MW, Yen R, Gannon CL, Griffith D, Chamberland S, Lomovskaya O, Hecker SJ, Lee VJ, Ohta T, Nakayama K. 1999. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J. Med. Chem. 42:4928-4931. http://dx.doi.org/10.1021/jm9904598.
21. Renau TE, Leger R, Flamme EM, She MW, Gannon CL, Mathias KM, Lomovskaya O, Chamberland S, Lee VJ, Ohta T, Nakayama K, Ishida Y. 2001. Addressing the stability of C-capped dipeptide efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett. 11:663-667. http://dx.doi.org/10.1016/S0960-894X(01)00033-6.
22. Renau TE, Leger R, Yen R, She MW, Flamme EM, Sangalang J, Gannon CL, Chamberland S, Lomovskaya O, Lee VJ. 2002. Peptidomimetics of efflux pump inhibitors potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett. 12:763-766. http://dx.doi.org/10.1016/S0960-894X(02) 00006-9.
23. Watkins WJ, Landaverry Y, Leger R, Litman R, Renau TE, Williams N, Yen R, Zhang JZ, Chamberland S, Madsen D, Griffith D, Tembe V, Huie K, Dudley MN. 2003. The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors. Bioorg. Med. Chem. Lett. 13:4241-4244. http://dx.doi.org/10.1016/j. bmcl.2003.07.030.
24. Lomovskaya O, Bostian KA. 2006. Practical applications and feasibility of efflux pump inhibitors in the clinic: a vision for applied use. Biochem. Pharmacol. 71:910-918. http://dx.doi.org/10.1016/j.bcp.2005.12.008.
25. Nakayama K, Ishida Y, Ohtsuka M, Kawato H, Yoshida K, Yokomizo Y, Hosono S, Ohta T, Hoshino K, Ishida H, Yoshida K, Renau TE, Leger R, Zhang JZ, Lee VJ, Watkins WJ. 2003. MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization. Bioorg. Med. Chem. Lett. 13:4201-4204. http://dx.doi.org/10.1016/j.bmcl.2003.07. 024.
26. Nakayama K, Ishida Y, Ohtsuka M, Kawato H, Yoshida K, Yokomizo Y, Ohta T, Hoshino K, Otani T, Kurosaka Y, Yoshida K, Ishida H, Lee VJ, Renau TE, Watkins WJ. 2003. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: achieving activity in vivo through the use of alternative scaffolds. Bioorg. Med. Chem. Lett. 13:4205-4208. http://dx.doi.org/10.1016/j.bmcl.2003.07. 027.
27. Nakayama K, Kawato H, Watanabe J, Ohtsuka M, Yoshida K, Yokomizo Y, Sakamoto A, Kuru N, Ohta T, Hoshino K, Yoshida K, Ishida H, Cho A, Palme MH, Zhang JZ, Lee VJ, Watkins WJ. 2004. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 3: optimization of potency in the pyridopyrimidine series through the application of a pharmacophore model. Bioorg. Med. Chem. Lett. 14:475-479. http://dx.doi.org/10.1016/j.bmcl.2003.10. 060.
28. Nakayama K, Kuru N, Ohtsuka M, Yokomizo Y, Sakamoto A, Kawato H, Yoshida K, Ohta T, Hoshino K, Akimoto K, Itoh J, Ishida H, Cho A, Palme MH, Zhang JZ, Lee VJ, Watkins WJ. 2004. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety. Bioorg. Med. Chem. Lett. 14:2493-2497. http://dx.doi.org/10.1016/j.bmcl.2004.03.007.
29. Yoshida K, Nakayama K, Kuru N, Kobayashi S, Ohtsuka M, Takemura M, Hoshino K, Kanda H, Zhang JZ, Lee VJ, Watkins WJ. 2006. MexABOprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 5: carbon-substituted analogues at the C-2 position. Bioorg. Med. Chem. 14:1993-2004. http://dx.doi.org/10.1016/j.bmc.2005.10.043.
30. Yoshida K, Nakayama K, Yokomizo Y, Ohtsuka M, Takemura M, Hoshino K, Kanda H, Namba K, Nitanai H, Zhang JZ, Lee VJ, Watkins WJ. 2006. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: exploration of aromatic substituents. Bioorg. Med. Chem. 14:8506-8518. http://dx.doi.org/10. 1016/j.bmc.2006.08.037.
31. Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H. 2006. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2:2006.0008. http://dx.doi.org/10.1038/msb4100050.
32. Clinical and Laboratory Standards Institute. 2006. Method for dilution antimicrobial susceptibility testing for bacteria that grow aerobically; approved standard M7-A7. Clinical and Laboratory Standards Institute, Wayne, PA.
33. Pillai SK, Moellering RC, Eliopoulos GM. 2005. Antimicrobial combinations, p 365-440. In Lorian V (ed), Antibiotics in laboratory medicine, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.
34. Coldham NG, Webber M, Woodward MJ, Piddock LJ. 2010. A 96-well plate fluorescence assay for assessment of cellular permeability and active efflux in Salmonella enterica serovar Typhimurium and Escherichia coli. J. Antimicrob. Chemother. 65:1655-1663. http://dx.doi.org/10.1093/jac/dkq169.
35. Nagano K, Nikaido H. 2009. Kinetic behavior of the major multidrug efflux pump AcrB of Escherichia coli. Proc. Natl. Acad. Sci. U. S. A. 106: 5854-5858. http://dx.doi.org/10.1073/pnas.0901695106.
36. Bohnert JA, Karamian B, Nikaido H. 2010. Optimized Nile Red efflux assay of AcrAB-TolC multidrug efflux system shows competition between substrates. Antimicrob. Agents Chemother. 54:3770-3775. http://dx.doi.org/10.1128/AAC.00620- 10.
37. Butler MM, Lamarr WA, Foster KA, Barnes MH, Skow DJ, Lyden PT, Kustigian LM, Zhi C, Brown NC, Wright GE, Bowlin TL. 2007. Antibacterial activity and mechanism of action of a novel anilinouracilfluoroquinolone hybrid compound. Antimicrob. Agents Chemother. 51: 119-127. http://dx.doi.org/10.1128/AAC.01311- 05.
38. Schumacher A, Steinke P, Bohnert JA, Akova M, Jonas D, Kern WV. 2006. Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Enterobacteriaceae other than Escherichia coli. J. Antimicrob. Chemother. 57:344-348. http://dx.doi.org/10.1093/jac/dki446.
39. Okusu H, Ma D, Nikaido H. 1996. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multipleantibiotic- resistance (Mar) mutants. J. Bacteriol. 178:306-308.
40. Ma D, Alberti M, Lynch C, Nikaido H, Hearst JE. 1996. The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals. Mol. Microbiol. 19:101-112. http://dx.doi.org/10. 1046/j.1365-2958.1996.357881.x.
41. Zgurskaya HI, Nikaido H. 1999. Bypassing the periplasm: reconstitution of the AcrAB multidrug efflux pump of Escherichia coli. Proc. Natl. Acad. Sci. U. S. A. 96:7190-7195. http://dx.doi.org/10.1073/pnas.96.13.7190.
42. Patel L, Garcia ML, Kaback HR. 1982. Direct measurement of lactose/ proton symport in Escherichia coli membrane vesicles: further evidence for the involvement of histidine residue(s). Biochemistry 21:5805-5810. http://dx.doi.org/10.1021/bi00266a013.
43. Eicher T, Cha HJ, Seeger MA, Brandstatter L, El-Delik J, Bohnert JA, Kern WV, Verrey F, Grutter MG, Diederichs K, Pos KM. 2012. Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop. Proc. Natl. Acad. Sci. U. S. A. 109:5687-5692. http://dx.doi.org/10.1073/pnas.1114944109.
44. Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A. 2006. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443:173-179. http://dx.doi.org/10.1038/nature05076.
45. Takatsuka Y, Chen C, Nikaido H. 2010. Mechanism of recognition of compounds of diverse structures by the multidrug efflux pump AcrB of Escherichia coli. Proc. Natl. Acad. Sci. U. S. A. 107:6559-6565. http://dx.doi.org/10.1073/ pnas.1001460107.
46. Vargiu AV, Nikaido H. 2012. Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations. Proc. Natl. Acad. Sci. U. S. A. 109:20637-20642. http://dx.doi.org/10.1073/pnas.1218348109.
47. Nakashima R, Sakurai K, Yamasaki S, Nishino K, Yamaguchi A. 2011. Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature 480:565-569. http://dx.doi.org/10.1038/nature10641.
48. Pages JM, Amaral L. 2009. Mechanisms of drug efflux and strategies to combat them: challenging the efflux pump of Gram-negative bacteria. Biochim. Biophys. Acta 1794:826-833. http://dx.doi.org/10.1016/j.bbapap.2008.12.011.
49. Sennhauser G, Bukowska MA, Briand C, Grutter MG. 2009. Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. J. Mol. Biol. 389:134-145. http://dx.doi.org/10.1016/j.jmb.2009.04.001.
50. Tikhonova EB, Wang Q, Zgurskaya HI. 2002. Chimeric analysis of the multicomponent multidrug efflux transporters from Gram-negative bacteria. J. Bacteriol. 184:6499-6507. http://dx.doi.org/10.1128/JB.184.23.6499-6507.2002.
51. Dewitt SK, Adelberg EA. 1962. The occurrence of a genetic transposition in a strain of Escherichia coli. Genetics 47:577-585.
52. Soupene E, van Heeswijk WC, Plumbridge J, Stewart V, Bertenthal D, Lee H, Prasad G, Paliy O, Charernnoppakul P, Kustu S. 2003. Physiological studies of Escherichia coli strain MG1655: growth defects and apparent cross-regulation of gene expression. J. Bacteriol. 185:5611-5626. http://dx.doi.org/10.1128/JB.185. 18.5611-5626.2003.
53. Holloway BW. 1955. Genetic recombination in Pseudomonas aeruginosa. J. Gen. Microbiol. 13:572-581. http://dx.doi.org/10.1099/00221287-13-3-572.