Multidrug-resistance efflux pumps - Not just for resistance

Nature Reviews Microbiology

Volumn 4, Issue 8, 2006, Pages 629-636

  Piddock, Laura J V ^a  

^a UNIVERSITY OF BIRMINGHAM   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ABC TRANSPORTER; ACRIFLAVINE; ANTIINFECTIVE AGENT; BETA LACTAM ANTIBIOTIC; CARRIER PROTEIN; CEFTAZIDIME; CEFTRIAXONE; CEPHALOSPORIN DERIVATIVE; CHLORAMPHENICOL; CIPROFLOXACIN; COTRIMOXAZOLE; ERYTHROMYCIN; ETHIDIUM BROMIDE; FUSIDIC ACID; GENTAMICIN; HORMONE; IMIPENEM; MEMBRANE PROTEIN; MULTIDRUG RESISTANCE PROTEIN; NITROFURANTOIN; OXAZOLIDINONE DERIVATIVE; PEPTIDE DEFORMYLASE INHIBITOR; PIPERACILLIN PLUS TAZOBACTAM; QUINOLINE DERIVED ANTIINFECTIVE AGENT; RESISTANCE NODULATION DIVISION PROTEIN; TETRACYCLINE; TIGECYCLINE; TIMENTIN; TOBRAMYCIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; ACRAB TOLC PROTEIN, SALMONELLA ENTERICA; ACRAB-TOLC PROTEIN, SALMONELLA ENTERICA; BACTERIAL PROTEIN; ESCHERICHIA COLI PROTEIN; MEXA PROTEIN, PSEUDOMONAS AERUGINOSA; MEXB PROTEIN, PSEUDOMONAS AERUGINOSA; OUTER MEMBRANE PROTEIN; TOLC PROTEIN, E COLI;

ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; ANTIBIOTIC SENSITIVITY; ARTICLE; BACTERIAL COLONIZATION; BACTERIAL GENE; BACTERIAL IMMUNITY; BACTERIAL INFECTION; BACTERIAL MEMBRANE; BACTERIAL METABOLISM; BACTERIAL SURVIVAL; BACTERIAL VIRULENCE; BILE; CELL MEMBRANE PERMEABILITY; CELL MEMBRANE TRANSPORT; DIARRHEA; DRUG SPECIFICITY; GASTROENTERITIS; GENE OVEREXPRESSION; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; HOST RESISTANCE; HUMAN; MINIMUM INHIBITORY CONCENTRATION; MULTIDRUG RESISTANCE; NONHUMAN; OPPORTUNISTIC INFECTION; PRIORITY JOURNAL; SALMONELLOSIS; BACTERIAL PHENOMENA AND FUNCTIONS; BACTERIUM; GENETICS; MICROBIOLOGICAL EXAMINATION; PATHOGENICITY; PHYSIOLOGY; REVIEW; VIRULENCE;

BACTERIA (MICROORGANISMS);

ATP-BINDING CASSETTE TRANSPORTERS; BACTERIA; BACTERIAL OUTER MEMBRANE PROTEINS; BACTERIAL PHYSIOLOGY; BACTERIAL PROTEINS; CARRIER PROTEINS; DRUG RESISTANCE, MULTIPLE, BACTERIAL; ESCHERICHIA COLI PROTEINS; MEMBRANE TRANSPORT PROTEINS; MICROBIAL SENSITIVITY TESTS; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; VIRULENCE;

EID: 33747154459     PISSN: 17401526     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrmicro1464     Document Type: Article

References (95)

1. Borges-Walmsley, M. I., McKeegan, K. S. & Walmsley, A. R. Structure and function of efflux pumps that confer resistance to drugs. Biochem. J. 376, 313-338 (2003).
2. Paulsen, I. T. Multidrug efflux pumps and resistance: Regulation and evolution. Curr. Opin. Microbiol. 6, 446-451 (2003).
3. Li, X. & Nikaido, H. Efflux mediated drug resistance in bacteria. Drugs 64, 159-204 (2004).
4. Poole, K. Efflux mediated multi-resistance in Gram-negative bacteria. Clin. Microbiol. Infect. 10, 12-26 (2004).
5. Poole, K. Efflux mediated antimicrobial resistance. J. Antimicrob. Chemother. 56, 20-51 (2005).
6. Hooper, D. C. Efflux pumps and nosocomial antibiotic resistance: A primer for hospital epidemiologists. Clin. Infect. Dis. 40, 1811-1817 (2005).
7. Piddock, L. J. V. Clinically relevant bacterial chromosomally encoded multi-drug resistance efflux pumps. Clin. Microbiol. Rev. 19, 382-402 (2006).
8. Ramos, J. L. et al. The TetR family of transcriptional repressors. Microbiol. Mol. Biol. Rev. 69, 326-356 (2005).
9. Koronakis, V., Eswaran, J. & Hughes, C. Structure and function of TolC: the bacterial exit duct for proteins and drugs. Annu. Rev. Biochem. 73, 467-489 (2004).
10. Aires, J. R. & Nikaido, H. Aminoglycosides are captured from both periplasm and cytoplasm by the AcrD multidrug efflux transporter of Escherichia coli. J. Bacteriol. 187, 1923-1929 (2005).
11. Eswaran, J., Koronakis, E., Higgins, M. K., Hughes, C. & Koronakis, V. Three's company: Component structures bring a closer view of tripartite drug efflux pumps. Curr. Opin. Struct. Biol. 14, 741-747 (2004).
12. Li, X. Z., Livermore, D. M. & Nikaido, H. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: Resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob. Agents Chemother. 38, 1732-1741 (1994).
13. Poole, K., Krebes, K., McNally, C. & Neshat, S. Multiple antibiotic resistance in Pseudomonas aeruginosa: Evidence for involvement of an efflux operon. J. Bacteriol. 175, 7363-7372 (1993).
14. Livermore, D. L. Linezolid in vitro: Mechanism and antibacterial spectrum. J. Antimicrob. Chemother. 51, 9-16 (2003).
15. Johnson, K. W., Lofland, D. & Moser, H. E. PDF inhibitors: An emerging class of antibacterial drugs. Curr. Drug Targets Infect. Disord. 5, 39-52 (2005).
16. Buysse, J. M. et al. Mutation of the AcrAB antibiotic efflux pump in Escherichia coli confers susceptibility to oxazolidinone antibiotics. Abstract C-42. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy (New Orleans, Louisiana, USA, 15-18 Sep 1996).
17. Chollet, R., Chevalier, J., Bryskier, A. & Pages, J. M. The AcrAB-TolC pump is involved in macrolide resistance but not in telithromycin efflux in Enterobacter aerogenes and Escherichia coli. Antimicrob. Agents Chemother. 48, 3621-3624 (2004).
18. Peric, M., Bozdogan, B., Jacobs, M. R. & Appelbaum, P. C. Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates. Antimicrob. Agents Chemother. 47, 1017-1022 (2003).
19. Sanchez, L., Pan, W., Vinas, M. & Nikaido, H. The acrAB homolog of Haemophilus influenzae codes for a functional multidrug efflux pump. J. Bacteriol. 179, 6855-6857 (1997).
20. Dean, C. R., Visalli, M. A., Projan, S. J., Sum, P. E. & Bradford. P. A. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob. Agents Chemother. 47, 972-978 (2003).
21. Visalli, M. A., Murphy, E., Projan, S. J. & Bradford, P. A. AcrAB multidrug efflux pump is associated with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis. Antimicrob. Agents Chemother. 47, 665-669 (2003).
22. Poole, K. & Srikumar, R. Multidrug efflux in Pseudomonas aeruginosa: components, mechanisms and clinical significance. Curr. Top. Med. Chem. 1, 59-71 (2001).
23. Matsuda, N. et al. Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-OprM efflux pumps in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44, 3322-3327 (2000).
24. Ziha-Zarifi, I., Llanes, C., Köhler, T., Pechère, J.-C. & Plésiat, P. In vivo emergence of multidrug-resistant mutants of Pseudomonas aeruginosa overexpressing the active efflux system MexA-MexB-OprM. Antimicrob. Agents Chemother. 43, 287-291 (1999).
25. Oh, H., Stenhoff, J., Jalal, S. & Wretlind, B. Role of efflux pumps and mutations in genes for topoisomerases II and IV in fluoroquinolone-resistant Pseudomonas aeruginosa strains. Microb. Drug Resist. 9, 323-328 (2003).
26. Hocquet, D., Bertand, X., Kohler, T., Talon, D. & Plésiat, P. Genetic and phenotypic variations of a resistant Pseudomonas aeruginosa epidemic clone. Antimicrob. Agents Chemother. 47, 1887-1894 (2003).
27. Okusu, H., Ma, D. & Nikaido, H. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. J. Bacteriol. 178, 306-308 (1996).
28. Nikaido, H. Multiple antibiotic resistance and efflux. Curr. Opin. Microbiol. 1, 515-523 (1998).
29. Fernandes, P., Ferreira, B. S. & Cabral, J. M. Solvent tolerance in bacteria: Role of efflux pumps and cross-resistance with antibiotics. Int. J. Antimicrob. Agents 22, 211-216 (2003).
30. White, D. G., Goldman, J. D., Demple B. & Levy, S. B. Role of the acrAB locus in organic solvent tolerance mediated by expression of marA, soxS, or robA in Escherichia coli. J. Bacteriol. 179, 6122-6126 (1997).
31. Rosenberg, E. Y., Ma, D. & Nikaido, H. AcrD of Escherichia coli is an aminoglycoside efflux pump. J. Bacteriol. 182, 1754-1756 (2000).
32. Zgurskaya, H. I. & Nikaido, H. Multidrug resistance mechanisms: Drug efflux across two membranes. Mol. Microbiol. 37, 219-225 (2000).
33. Nishino, K. & Yamaguchi, A. Analysis of the complete library of putative drug transporter genes in Escherichia coli. J. Bacteriol. 183, 5803-5812 (2001).
34. Mazzariol, A., Tokue, Y., Kanegawa, T. M., Cornaglia, G. & Nikaido, H. High level fluoroquinolone resistant clinical isolates of Escherichia coli over produce multidrug efflux protein AcrA. Antimicrob. Agents Chemother. 44, 3441-3443 (2000); erratum in 45, 647 (2001).
35. Oethinger, M., Kern, W. V., Jellen-Ritter, A. S., McMurry L. M. & Levy, S. B. Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump. Antimicrob. Agents Chemother. 44, 10-13 (2000).
36. Webber, M. A. & Piddock, L. J. V. Absence of mutations in marAB or soxRS in acrB-overexpressing fluoroquinolone-resistant clinical and veterinary isolates of Escherichia coli. Antimicrob. Agents Chemother. 45, 1550-1552 (2001).
37. Everett, M. J., Jin, Y.-F., Ricci, V. & Piddock, L. J. V. Contribution of individual mechanisms to fluoroquinolone resistance in 36 Escherichia coli isolated from humans and animals. Antimicrob. Agents Chemother. 40, 2380-2386 (1996).
38. Eaves, D. J., Ricci, V. & Piddock, L. J. Expression of acrB, acrF, acrD, marA, and soxS in Salmonella enterica serovar Typhimurium: Role in multiple antibiotic resistance. Antimicrob. Agents Chemother. 48, 1145-1150 (2004).
39. Baucheron, S. et al. AcrAB-TolC directs efflux-mediated multidrug resistance in Salmonella enterica serovar Typhimurium DT104. Antimicrob. Agents Chemother. 48, 3729-3735 (2004).
40. Nishino, K., Latifi, T. & Groisman, E. A. Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium. Mol. Microbiol. 59, 126-141 (2006).
41. Giraud, E., Cloeckaert, A., Kerboeuf, D. & Chaslus-Dancla, E. Evidence for active efflux as the primary mechanism of resistance to ciprofloxacin in Salmonella enterica serovar Typhimurium. Antimicrob. Agents Chemother. 44, 1223-1228 (2000).
42. Piddock, L. V. J., White, D. G., Gensberg, K., Pumbwe, L. & Griggs, D. J. Evidence for an efflux pump mediating multiple antibiotic resistance in Salmonella enterica serovar Typhimurium. Antimicrob. Agents Chemother. 44, 3118-3121 (2000).
43. Piddock, L. J. V., Griggs, D. J., Hall, M. C. & Jin, Y. F. Ciprofoxacin resistance in clinical isolates of Salmonella typhimurium obtained from two patients. Antimicrob. Agents Chemother. 37, 662-666 (1993).
44. Wain, J. et al. Quinolone-resistant Salmonella typhi in Viet Nam: Basis of resistance and clinical response to treatment. Clin. Infect. Dis. 25, 1404-1410 (1997).
45. Molbak, K. et al. An outbreak of multidrug-resistant, quinolone-resistant, Salmonella enterica serotype Typhimurium DT104. N. Engl. J. Med. 341, 1420-1425 (1999).
46. Pumbwe, L. & Piddock, L. J. V. Identification and molecular characterisation of CmeB, a Campylobacter jejuni multidrug efflux pump. FEMS Microbiol. Lett. 206, 185-189 (2002).
47. Lin, J., Overbye, L. M. & Zhang, Q. CmeABC functions as a multidrug efflux system in Campylobacter jejuni. Antimicrob. Agents Chemother. 46, 2124-2131 (2002).
48. Pumbwe, L., Randall, L. P., Woodward, M. J. & Piddock, L. J. V. Expression of the efflux pump genes cmeB, cmeF and the porin gene porA in multiply antibiotic-resistant Campylobacter spp. J. Antimicrob. Chemother. 54, 341-347 (2004).
49. Pumbwe, L., Randall, L. P., Woodward, M. J. & Piddock, L. J. V. Evidence for multiple antibiotic resistance in Campylobacter jejuni not mediated by CmeB or CmeF. Antimicrob. Agents Chemother. 49, 1289-1293 (2005).
50. Lin, J., Sahin, O., Michel, L. O. & Zhang, Q. Critical role of multi-drug efflux pump CmeABC in bile resistance and in vivo colonisation of Campylobacter jejuni. Infect. Immun. 71, 4250-4259 (2003).
51. Veal, W. L., Nicholas, R. A. & Shafer, W. M. Overexpression of the MtrC-MtrD-MtrE efflux pump due to an mtrR mutation is required for chromosomally mediated penicillin resistance in Neisseria gonorrhoeae. J. Bacteriol. 184, 5619-5624 (2002).
52. Neyfakh, A. A. The multidrug efflux transporter of Bacillus subtilis is a structural and functional homolog of the Staphylococcus NorA protein. Antimicrob. Agents Chemother. 36, 484-485 (1992).
53. Yoshida, H., Bogaki, M., Nakamura, S., Ubukata, K. & Konno, M. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J. Bacteriol. 172, 6942-6949 (1990).
54. Neyfakh, A. A., Borsch, C. M. & Kaatz, G. W. Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter. Antimicrob. Agents Chemother. 37, 128-129 (1993).
55. Kaatz, G. W., Seo, S. M. & Ruble, C. A. Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 37, 1086-1094 (1993).
56. Ng, E. Y., Truckis, M. & Hooper, D. C. Quinolone resistance mediated by norA: Physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome. Antimicrob. Agents Chemother. 38, 1345-1355 (1994).
57. Jones, M. E., Boenink, N. M., Verhoef, J., Kohrer, K. & Schmitz, F.-J. Multiple mutations conferring ciprofloxacin resistance in Staphylococcus aureus demonstrate the long term stability in an antibiotic-free environment. J. Antimicrob. Chemother. 45, 353-356 (2000).
58. Noguchi, N., Okada, H., Narui, K. & Sasatsu, M. Comparison of the nucleotide sequence and expression of norA genes and microbial susceptibility in 21 strains of Staphylococcus aureus. Microb. Drug Resist. 10, 197-203 (2004).
59. Schmitz, F.-J. et al. Relationship between mutations in the coding and promoter regions of the norA genes in 42 unrelated clinical isolates of Staphylococcus aureus and the MICs of norfloxacin for these strains. J. Antimicrob. Chemother. 42, 561-563 (1998).
60. Oizumi, N. et al. Relationship between mutations in the DNA gyrase and topoisomerase IV genes and nadifloxacin resistance in clinically isolated quinolone-resistant Staphylococcus aureus. J. Infect. Chemother. 7, 191-194 (2001).
61. Gill, M. J., Brenwald, N. P. & Wise, R. Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 43, 187-189 (1999).
62. Piddock, L. J. V., Johnson, M. M., Simjee, S. & Pumbwe, L. Expression of efflux pump gene pmrA in fluoroquinolone-resistant and -susceptible clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 46, 808-812 (2002).
63. Marrer, E. et al. Involvement of the putative ATP-dependent efflux proteins PatA and PatB in fluoroquinolone resistance of a multidrug-resistant mutant of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 50, 685-693 (2006).
64. Ambrose, K D., Nisbet. R. & Stephens, D. S. Macrolide efflux in Streptococcus pneumoniae is mediated by a dual efflux pump (mel and mef) and is erythromycin inducible. Antimicrob. Agents Chemother. 49, 4203-4209 (2005).
65. Stone, B. J. & Miller, V. L. Salmonella enteritidis has a homologue of tolC that is required for virulence in BALB/c mice. Mol. Microbiol. 17, 701-712 (1995).
66. Lacroix, F. J. C. et al. Salmonella typhimurium acrB-like gene: identification and role in resistance to biliary salts and detergents and in murine infection. FEMS Microbiol. Lett. 135, 161-167 (1996).
67. Baucheron, S., Mouline, C., Praud, K., Chaslus-Dancla, E. & Cloeckaert, A. TolC but not AcrB is essential for multidrug-resistant Salmonella enterica serotype Typhimurium colonization of chicks. J. Antimicrob. Chemother. 55, 707-712 (2005).
68. Buckley, A. M. et al. The AcrAB-TolC efflux system of Salmonella enterica serovar Typhimurium plays a role in pathogenesis. Cell. Microbiol. 8, 847-856 (2006).
69. Hirakata, Y. et al. Multidrug efflux systems play an important role in the invasiveness of Pseudomonas aeruginosa. J. Exp. Med. 196, 109-118 (2002).
70. Jerse, A. E. et al. A gonococcal efflux pump system enhances bacterial survival in a female mouse model of genital tract infection. Infect. Immun. 71, 5576-5582 (2003).
71. Burse, A., Weingart, H. & Ullrich, M. S. The phytoalexin-inducible multidrug efflux pump AcrAB contributes to virulence in the fire blight pathogen, Erwinia amylovora. Mol. Plant Microbe Interact. 17, 43-54 (2004).
72. Burse, A., Weingart, H. & Ullrich, M. S. NorM, an Erwinia amylovora multidrug efflux pump involved in in vitro competition with other epiphytic bacteria. Appl. Environ. Microbiol. 70, 693-703 (2004).
73. Koronakis, V. & Hughes, C. Synthesis, maturation and export of the E. coli hemolysin. Med. Microbiol. Immunol. (Berl.) 185, 65-71 (1996).
74. Binet, R., Letoffe, S., Ghigo, J. M., Delepelaire, P. & Wandersman, C. Protein secretion by Gram-negative bacterial ABC exporters - a review. Gene 192, 7-11 (1997).
75. Bhakdi, S. et al. The hemolysin of Escherichia coli. Eur. J. Epidemiol. 4, 135-143 (1988).
76. Gilson, L., Mahanty H. K. & Kolter, R. Genetic analysis of an MDR-like export system: The secretion of colicin V. EMBO J. 9, 3875-3894 (1990).
77. Bina, J. E. & Mekalanos. J. J. Vibrio cholerae tolC is required for bile resistance and colonization. Infect. Immun. 69, 4681-4685 (2001).
78. Boardman, B. K. & Satchell, K. J. Vibrio cholerae strains with mutations in an atypical type I secretion system accumulate RTX toxin intracellularly. J. Bacteriol. 186, 8137-8143 (2004).
79. Join-Lambert, O. F. et al. Differential selection of multidrug efflux mutants by trovafloxacin and ciprofloxacin in an experimental model of Pseudomonas aeruginosa acute pneumonia in rats. Antimicrob. Agents Chemother. 45, 571-576 (2001).
80. Lee, V. T. & Schneewind, O. Protein secretion and the pathogenesis of bacterial infections. Genes Dev. 15, 1725-1752 (2001).
81. Groisman, E. A., Eduardo, A. & Mouslim, C. Molecular mechanisms of Salmonella pathogenesis. Curr. Opin. Infect. Dis. 13, 519-522 (2000).
82. Evans, K. et al. Influence of the MexAB-OprM multidrug efflux system on quorum sensing in Pseudomonas aeruginosa. J. Bacteriol. 180, 5443-5447 (1998).
83. Keller, L. & Surette, M. G. Communication in bacteria: An ecological and evolutionary perspective. Nature Rev. Microbiol. 4, 249-258 (2006).
84. Sanchez, P. et al. Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants. J. Antimicrob. Chemother. 50, 657-664 (2002).
85. Yang, S., Lopez, C. R. & Zechiedrich, E. L. Quorum sensing and multi-drug transporters in Escherichia coli. Proc. Natl Acad. Sci. USA 103, 2386-2391 (2006).
86. Linares, J. F. et al. Overexpression of the multidrug efflux pumps MexCD-OprJ and MexEF-OprN is associated with a reduction of type III secretion in Pseudomonas aeruginosa. J. Bacteriol. 187, 1384-1391 (2005).
87. Ma, D. et al. Genes acrA and acrB encode a stress-induced efflux system of Escherichia coli. Mol. Microbiol. 16, 45-55 (1995).
88. Nikaido, H., Basina, V., Nguyen, V. & Rosenberg, E. Y. Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those β-lactam antibiotics containing lipophilic side chains. J. Bacteriol. 180, 4686-4692 (1998).
89. Prouty, A. M., Brodsky, I. E., Falkow, S. & Gunn, J. S. Bile-salt-mediated induction of antimicrobial and bile resistance in Salmonella typhimurium. Microbiology 150, 775-783 (2004).
90. Rouquette, C., Harmon, J. B. & Shafer, W. M. Induction of the mtrCDE-encoded efflux pump system of Neisseria gonorrhoeae requires MtrA, an AraC-like protein. Mol. Microbiol. 33, 651-658 (1999).
91. Elkins, C. A. & Mullis, L. B. Mammalian steroid hormones are substrates for the major RND- and MFS-type tripartite multidrug efflux pumps of Escherichia coli. J. Bacteriol. 188, 1191-1195 (2006).
92. Shafer, W. M., Qu, X.-D., Waring, A. J. & Lehrer, R. I. Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proc. Natl Acad. Sci. USA 95, 1829-1833 (1998).
93. Sulavik, M. C. et al. Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes. Antimicrob. Agents Chemother. 45, 1126-1136 (2001).
94. Kaatz, G. W. & Seo, S. M. Mechanisms of fluoroquinolone resistance in genetically related strains of Staphylococcus aureus. Antimicrob. Agents Chemother. 41, 2733-2737 (1997).
95. Hsieh, P.-C., Siegel, S. A., Rogers, B., Davis, D. & Lewis, K. Bacteria lacking a multidrug pump: A sensitive tool for drug discovery. Proc. Natl Acad. Sci. USA 95, 6602-6606 (1998).