Efflux pumps as an important mechanism for quinolone resistance

Advances in Enzymology and Related Areas of Molecular Biology

Volumn 77 1, Issue , 2010, Pages 167-235

  Vila, Jordi ^a   Fábrega, Anna ^a   Roca, Ignasi ^a   Hernández, Alvaro ^b   Martínez, José Luis ^b  

^a UNIVERSITY OF BARCELONA   (Spain)

^b CSIC   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFECTIVE AGENT; CARRIER PROTEIN; QUINOLINE DERIVATIVE;

ANIMAL; BACTERIAL GENE; BIOLOGICAL MODEL; ENTEROBACTERIACEAE; GENETICS; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; HUMAN; METABOLISM; MULTIDRUG RESISTANCE; MUTATION; PLASMID; REVIEW; SPECIES DIFFERENCE;

ANIMALS; ANTI-BACTERIAL AGENTS; DRUG RESISTANCE, MULTIPLE, BACTERIAL; ENTEROBACTERIACEAE; GENES, BACTERIAL; GRAM-NEGATIVE BACTERIA; GRAM-POSITIVE BACTERIA; HUMANS; MEMBRANE TRANSPORT PROTEINS; MODELS, BIOLOGICAL; MUTATION; PLASMIDS; QUINOLINES; SPECIES SPECIFICITY;

EID: 79960936596     PISSN: 0065258X     EISSN: None     Source Type: Book Series    
DOI: None     Document Type: Article

References (269)

1. Vila, J. (2005) Fluoroquinolone resistance, in Frontiers in Antimicrobial Resistance: A Tribute to Stuart B. Levy, White, D. G., Alekshun, M. N., and MacDermott, P. F., Eds., ASM Press, Washington, DC, pp. 41-52.
2. Fabrega, A., Madurga, S., Giralt, E., and Vila, J. (2009) Mechanism of action of and resistance to quinolones, Microb. Biotechnol. 2, 40-61.
3. Levy, S. B. (1992) Active efflux mechanisms for antimicrobial resistance, Antimicrob. Agents Chemother. 36, 695-703.
4. Roca, I., Marti, S., Espinal, P., Martinez, P., Gibert, I., and Vila, J. (2009) CraA: an MFS efflux pump associated with chloramphenicol resistance in Acinetobacter baumannii, Antimicrob. Agents Chemother. 53, 4013-4014.
5. Piddock, L. J. (2006) Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria, Clin. Microbiol. Rev. 19, 382-402.
6. Nikaido, H. (1996) Multidrug efflux pumps of gram-negative bacteria, J. Bacteriol. 178, 5853-5859.
7. Nikaido, H. (1998) Antibiotic resistance caused by gram-negative multidrug efflux pumps, Clin. Infect. Dis. 27 (Suppl. 1), S32-S41.
8. Edgar, R., and Bibi, E. (1997) MdfA, an Escherichia coli multidrug resistance protein with an extraordinarily broad spectrum of drug recognition, J. Bacteriol. 179, 2274-2280.
9. Nishino, K., and Yamaguchi, A. (2001) Analysis of a complete library of putative drug transporter genes in Escherichia coli, J. Bacteriol. 183, 5803-5812.
10. Yang, S., Clayton, S. R., and Zechiedrich, E. L. (2003) Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone resistance in Escherichia coli, J. Antimicrob. Chemother. 51, 545-556.
11. Rosenberg, E. Y., Ma, D., and Nikaido, H. (2000) AcrD of Escherichia coli is an aminoglycoside efflux pump, J. Bacteriol. 182, 1754-1756.
12. Webber, M. A., and Piddock, L. J. (2001) Absence of mutations in marRAB or soxRS in acrB-overexpressing fluoroquinolone-resistant clinical and veterinary isolates of Escherichia coli, Antimicrob. Agents Chemother. 45, 1550-1552.
13. Oethinger, M., Kern, W. V., Jellen-Ritter, A. S., McMurry, L. M., and Levy, S. B. (2000) 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.
14. Okusu, H., Ma, D., and Nikaido, H. (1996) 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.
15. Fralick, J. A. (1996) Evidence that TolC is required for functioning of the Mar/AcrAB efflux pump of Escherichia coli, J. Bacteriol. 178, 5803-5805.
16. Sulavik, M. C., Houseweart, C., Cramer, C., Jiwani, N., Murgolo, N., Greene, J., DiDomenico, B., Shaw, K. J., Miller, G. H., Hare, R., and Shimer, G. (2001) Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes, Antimicrob. Agents Chemother. 45, 1126-1136.
17. Jellen-Ritter, A. S., and Kern, W. V. (2001) Enhanced expression of the multidrug efflux pumps AcrAB and AcrEF associated with insertion element transposition in Escherichia coli mutants selected with a fluoroquinolone, Antimicrob. Agents Chemother. 45, 1467-1472.
18. Kobayashi, K., Tsukagoshi, N., and Aono, R. (2001) Suppression of hypersensitivity of Escherichia coli acrB mutant to organic solvents by integrational activation of the acrEF operon with the IS1 or IS2 element, J. Bacteriol. 183, 2646-2653.
19. White, D. G., Goldman, J. D., Demple, B., and Levy, S. B. (1997) 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.
20. Gallegos, M. T., Schleif, R., Bairoch, A., Hofmann, K., and Ramos, J. L. (1997) Arac/ XylS family of transcriptional regulators, Microbiol. Mol. Biol. Rev. 61, 393-410.
21. George, A. M., and Levy, S. B. (1983) Gene in the major cotransduction gap of the Escherichia coli K-12 linkage map required for the expression of chromosomal resistance to tetracycline and other antibiotics, J. Bacteriol. 155, 541-548.
22. Wu, J., andWeiss, B. (1991) Two divergently transcribed genes, soxR and soxS, control a superoxide response regulon of Escherichia coli, J. Bacteriol. 173, 2864-2871.
23. Skarstad, K., Thony, B., Hwang, D. S., and Kornberg, A. (1993) A novel binding protein of the origin of the Escherichia coli chromosome, J. Biol. Chem. 268, 5365-5370.
24. Martin, R. G., Gillette, W. K., Rhee, S., and Rosner, J. L. (1999) Structural requirements for marbox function in transcriptional activation of mar/sox/rob regulon promoters in Escherichia coli: sequence, orientation and spatial relationship to the core promoter, Mol. Microbiol. 34, 431-441.
25. Martin, R. G., and Rosner, J. L. (2002) Genomics of the marA/soxS/rob regulon of Escherichia coli: identification of directly activated promoters by application of molecular genetics and informatics to microarray data, Mol. Microbiol. 44, 1611-1624.
26. Ma, D., Alberti, M., Lynch, C., Nikaido, H., and Hearst, J. E. (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.
27. Koutsolioutsou, A., Peña-Llopis, S., and Demple, B. (2005) Constitutive soxR mutations contribute to multiple-antibiotic resistance in clinical Escherichia coli isolates, Antimicrob. Agents Chemother. 49, 2746-2752.
28. Oethinger, M., Podglajen, I., Kern, W. V., and Levy, S. B. (1998) Overexpression of the marA or soxS regulatory gene in clinical topoisomerase mutants of Escherichia coli, Antimicrob. Agents Chemother. 42, 2089-2094.
29. Coburn, B., Grassl, G. A., and Finlay, B. B. (2007) Salmonella, the host and disease: a brief review, Immunol. Cell Biol. 85, 112-118.
30. Hohmann, E. L. (2001) Nontyphoidal salmonellosis, Clin. Infect. Dis. 32, 263-269.
31. Baucheron, S., Imberechts, H., Chaslus-Dancla, E., and Cloeckaert, A. (2002) The AcrB multidrug transporter plays a major role in high-level fluoroquinolone resistance in Salmonella enterica serovar typhimurium phage type DT204, Microb. Drug Resist. 8, 281-289.
32. Chen, S., Cui, S., McDermott, P. F., Zhao, S., White, D. G., Paulsen, I., and Meng, J. (2007) Contribution of target gene mutations and efflux to decreased susceptibility of Salmonella enterica serovar typhimurium to fluoroquinolones and other antimicrobials, Antimicrob. Agents Chemother. 51, 535-542.
33. Baucheron, S., Tyler, S., Boyd, D., Mulvey, M. R., Chaslus-Dancla, E., and Cloeckaert, A. (2004) AcrAB-TolC directs efflux-mediated multidrug resistance in Salmonella enterica serovar typhimurium DT104, Antimicrob. Agents Chemother. 48, 3729-3735.
34. Ricci, V., Tzakas, P., Buckley, A., and Piddock, L. J. (2006) Ciprofloxacin-resistant Salmonella enterica serovar typhimurium strains are difficult to select in the absence of AcrB and TolC, Antimicrob. Agents Chemother. 50, 38-42.
35. Olliver, A., Valle, M., Chaslus-Dancla, E., and Cloeckaert, A. (2005) Overexpression of the multidrug efflux operon acrEF by insertional activation with IS1 or IS10 elements in Salmonella enterica serovar typhimurium DT204 acrB mutants selected with fluoroquinolones, Antimicrob. Agents Chemother. 49, 289-301.
36. Pomposiello, P. J., and Demple, B. (2000) Identification of SoxS-regulated genes in Salmonella enterica serovar typhimurium, J. Bacteriol. 182, 23-29.
37. Sulavik, M. C., Dazer, M., and Miller, P. F. (1997) The Salmonella typhimurium mar locus: molecular and genetic analyses and assessment of its role in virulence, J. Bacteriol. 179, 1857-1866.
38. Piddock, L. J., White, D. G., Gensberg, K., Pumbwe, L., and Griggs, D. J. (2000) Evidence for an efflux pump mediating multiple antibiotic resistance in Salmonella enterica serovar typhimurium, Antimicrob. Agents Chemother. 44, 3118-3121.
39. Koutsolioutsou, A., Martins, E. A., White, D. G., Levy, S. B., and Demple, B. (2001) A soxRS-constitutive mutation contributing to antibiotic resistance in a clinical isolate of Salmonella enterica (serovar typhimurium), Antimicrob. Agents Chemother. 45, 38-43.
40. O'Regan, E., Quinn, T., Pagés, J. M., McCusker, M., Piddock, L., and Fanning, S. (2009) Multiple regulatory pathways associated with high-level ciprofloxacin and multi-drug resistance in Salmonella enterica serovar enteritidis: involvement of RamA and other global regulators, Antimicrob. Agents Chemother. 53, 1080-1087.
41. Olliver, A., Valle, M., Chaslus-Dancla, E., and Cloeckaert, A. (2004) Role of an acrR mutation in multidrug resistance of in vitro-selected fluoroquinolone-resistant mutants of Salmonella enterica serovar typhimurium, FEMS Microbiol. Lett. 238, 267-272.
42. Chu, C., Su, L. H., Chu, C. H., Baucheron, S., Cloeckaert, A., and Chiu, C. H. (2005) Resistance to fluoroquinolones linked to gyrA and parC mutations and overexpression of acrAB efflux pump in Salmonella enterica serotype choleraesuis, Microb. Drug Resist. 11, 248-253.
43. van der Straaten, T., Janssen, R., Mevius, D. J., and van Dissel, J. T. (2004) Salmonella gene rma (ramA) and multiple-drug-resistant Salmonella enterica serovar typhimurium, Antimicrob. Agents Chemother. 48, 2292-2294.
44. Abouzeed, Y. M., Baucheron, S., and Cloeckaert, A. (2008) ramR mutations involved in efflux-mediated multidrug resistance in Salmonella enterica serovar typhimurium, Antimicrob. Agents Chemother. 52, 2428-2434.
45. Deguchi, T., Kawamura, T., Yasuda, M., Nakano, M., Fukuda, H., Kato, H., Kato, N., Okano, Y., and Kawada, Y. (1997) In vivo selection of Klebsiella pneumoniae strains with enhanced quinolone resistance during fluoroquinolone treatment of urinary tract infections, Antimicrob. Agents Chemother. 41, 1609-1611.
46. Martínez-Martínez, L., Garcia, I., Ballesta, S., Benedi, V. J., Hernandez-Alles, S., and Pascual, A. (1998) Energy-dependent accumulation of fluoroquinolones in quinoloneresistant Klebsiella pneumoniae strains, Antimicrob. Agents Chemother. 42, 1850-1852.
47. Mazzariol, A., Zuliani, J., Cornaglia, G., Rossolini, G. M., and Fontana, R. (2002) AcrAB efflux system: expression and contribution to fluoroquinolone resistance in Klebsiella spp., Antimicrob. Agents Chemother. 46, 3984-3986.
48. Schneiders, T., Amyes, S. G., and Levy, S. B. (2003) Role of AcrR and ramA in fluoroquinolone resistance in clinical Klebsiella pneumoniae isolates from Singapore, Antimicrob. Agents Chemother. 47, 2831-2837.
49. George, A. M., Hall, R. M., and Stokes, H. W. (1995) Multidrug resistance in Klebsiella pneumoniae: a novel gene, ramA, confers a multidrug resistance phenotype in Escherichia coli, Microbiology 141(Pt. 8), 1909-1920.
50. Ruzin, A., Visalli, M.A., Keeney, D., andBradford, P. A. (2005) Influence of transcriptional activator RamA on expression of multidrug efflux pump AcrAB and tigecycline susceptibility in Klebsiella pneumoniae, Antimicrob. Agents Chemother. 49, 1017-1022.
51. Ogawa, W., Koterasawa, M., Kuroda, T., and Tsuchiya, T. (2006) KmrA multidrug efflux pump from Klebsiella pneumoniae, Biol. Pharm. Bull. 29, 550-553.
52. Ping, Y., Ogawa, W., Kuroda, T., and Tsuchiya, T. (2007) Gene cloning and characterization of KdeA, a multidrug efflux pump from Klebsiella pneumoniae, Biol. Pharm. Bull. 30, 1962-1964.
53. Mallea, M., Chevalier, J., Bornet, C., Eyraud, A., vin-Regli, A., Bollet, C., and Pagés, J. M. (1998) Porin alteration and active efflux: two in vivo drug resistance strategies used by Enterobacter aerogenes, Microbiology 144(Pt. 11), 3003-3009.
54. Pradel, E., and Pagés, J. M. (2002) The AcrAB-TolC efflux pump contributes to multidrug resistance in the nosocomial pathogen Enterobacter aerogenes, Antimicrob. Agents Chemother. 46, 2640-2643.
55. Chollet, R., Bollet, C., Chevalier, J., Mallea, M., Pagés, J. M., and vin-Regli, A. (2002) mar operon involved in multidrug resistance of Enterobacter aerogenes, Antimicrob. Agents Chemother. 46, 1093-1097.
56. Chollet, R., Chevalier, J., Bollet, C., Pagés, J. M., and vin-Regli, A. (2004) RamA is an alternate activator of the multidrug resistance cascade in Enterobacter aerogenes, Antimicrob. Agents Chemother. 48, 2518-2523.
57. Perez, A., Canle, D., Latasa, C., Poza, M., Beceiro, A., Tomas, M. M., Fernandez, A., Mallo, S., Perez, S., Molina, F., et al. (2007) Cloning, nucleotide sequencing, and analysis of the AcrAB-TolC efflux pump of Enterobacter cloacae and determination of its involvement in antibiotic resistance in a clinical isolate, Antimicrob. Agents Chemother. 51, 3247-3253.
58. Linde, H. J., Notka, F., Irtenkauf, C., Decker, J., Wild, J., Niller, H. H., Heisig, P., and Lehn, N. (2002) Increase in MICs of ciprofloxacin in vivo in two closely related clinical isolates of Enterobacter cloacae, J. Antimicrob. Chemother. 49, 625-630.
59. Kumar, A., and Worobec, E. A. (2002) Fluoroquinolone resistance of Serratia marcescens: involvement of a proton gradient-dependent efflux pump, J. Antimicrob. Chemother. 50, 593-596.
60. Chen, J., Kuroda, T., Huda, M. N., Mizushima, T., and Tsuchiya, T. (2003) An RND-type multidrug efflux pump SdeXY from Serratia marcescens, J. Antimicrob. Chemother. 52, 176-179.
61. Shahcheraghi, F., Minato, Y., Chen, J., Mizushima, T., Ogawa, W., Kuroda, T., and Tsuchiya, T. (2007) Molecular cloning and characterization of a multidrug efflux pump, SmfY, from Serratia marcescens, Biol. Pharm. Bull. 30, 798-800.
62. Matsuo, T., Chen, J., Minato, Y., Ogawa, W., Mizushima, T., Kuroda, T., and Tsuchiya, T. (2008) SmdAB, a heterodimeric ABC-type multidrug efflux pump, in Serratia marcescens, J. Bacteriol. 190, 648-654.
63. Visalli, M. A., Murphy, E., Projan, S. J., and Bradford, P. A. (2003) AcrAB multidrug efflux pump is associated with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis, Antimicrob. Agents Chemother. 47, 665-669.
64. Saito, R., Sato, K., Kumita, W., Inami, N., Nishiyama, H., Okamura, N., Moriya, K., and Koike, K. (2006) Role of type II topoisomerase mutations and AcrAB efflux pump in fluoroquinolone-resistant clinical isolates of Proteus mirabilis, J. Antimicrob. Chemother. 58, 673-677.
65. Ishii, H., Sato, K., Hoshino, K., Sato, M., Yamaguchi, A., Sawai, T., and Osada, Y. (1991) Active efflux of ofloxacin by a highly quinolone-resistant strain of Proteus vulgaris, J. Antimicrob. Chemother. 28, 827-836.
66. Ishida, H., Fuziwara, H., Kaibori, Y., Horiuchi, T., Sato, K., and Osada, Y. (1995) Cloning of multidrug resistance gene pqrA from Proteus vulgaris, Antimicrob. Agents Chemother. 39, 453-457.
67. Navia, M. M., Ruiz, J., Ribera, A., de Anta, M. T., and Vila, J. (1999) Analysis of the mechanisms of quinolone resistance in clinical isolates of Citrobacter freundii, J. Antimicrob. Chemother. 44, 743-748.
68. Tavío, M., Vila, J., Ruiz, J., Amicosante, G., Franceschini, N., Martín-Sánchez, A. M., and de Anta, M. T. (2000) In vitro selected fluoroquinolone-resistant mutants of Citrobacter freundii: analysis of the quinolone resistance acquisition, J. Antimicrob. Chemother. 45, 521-524.
69. Sánchez-Céspedes, J., and Vila, J. (2007) Partial characterisation of the acrAB locus in two Citrobacter freundii clinical isolates, Int. J. Antimicrob. Agents 30, 259-263.
70. Quinn, J. P. (1998) Clinical problems posed by multiresistant nonfermenting gramnegative pathogens, Clin. Infect. Dis. 27(Suppl. 1), S117-S124.
71. Ferrara, A. M. (2006) Potentially multidrug-resistant non-fermentative gram-negative pathogens causing nosocomial pneumonia, Int. J. Antimicrob. Agents 27, 183-195.
72. McGowan, J. E., Jr., (2006) Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum, Am. J. Infect. Control 34, S29-S37; discussion S64-S73.
73. Alonso, A., Rojo, F., and Martínez, J. L. (1999) Environmental and clinical isolates of Pseudomonas aeruginosa show pathogenic and biodegradative properties irrespective of their origin, Environ. Microbiol. 1, 421-430.
74. Morales, G., Wiehlmann, L., Gudowius, P., van Delden, C., Tummler, B., Martínez, J. L., and Rojo, F. (2004) Structure of Pseudomonas aeruginosa populations analyzed by single nucleotide polymorphism and pulsed-field gel electrophoresis genotyping, J. Bacteriol. 186, 4228-4237.
75. Martínez, J. L. (2008) Antibiotics and antibiotic resistance genes in natural environments, Science 321, 365-367.
76. Martínez, J. L., Fajardo, A., Garmendia, L., Hernández, A., Linares, J. F., Martínez-Solano, L., and Sánchez, M. B. (2009) A global view of antibiotic resistance, FEMS Microbiol. Rev. 33, 44-65.
77. Martínez, J. L., Sánchez, M. B., Martínez-Solano, L., Hernández, A., Garmendia, L., Fajardo, A., and Alvarez-Ortega, C. (2009) Functional role of bacterial multidrug efflux pumps in microbial natural ecosystems, FEMS Microbiol. Rev. 33, 430-449.
78. Li, X. Z., Nikaido, H., and Poole, K. (1995) Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa, Antimicrob. Agents Chemother. 39, 1948-1953.
79. Poole, K., Gotoh, N., Tsujimoto, H., Zhao, Q., Wada, A., Yamasaki, T., Neshat, S., Yamagishi, J., Li, X. Z., and Nishino, T. (1996) Overexpression of the mexC-mexD-oprJ efflux operon in nfxB-type multidrug-resistant strains of Pseudomonas aeruginosa, Mol. Microbiol. 21, 713-724.
80. Köhler, T., Michea-Hamzehpour, M., Henze, U., Gotoh, N., Curty, L. K., and Pechere, J. C. (1997) Characterization of MexE-MexF-OprN, a positively regulated multidrug efflux system of Pseudomonas aeruginosa, Mol. Microbiol. 23, 345-354.
81. Aires, J. R., Köhler, T., Nikaido, H., and Plésiat, P. (1999) Involvement of an active efflux system in the natural resistance of Pseudomonas aeruginosa to aminoglycosides, Antimicrob. Agents Chemother. 43, 2624-2628.
82. Mine, T., Morita, Y., Kataoka, A., Mizushima, T., and Tsuchiya, T. (1999) Expression in Escherichia coli of a new multidrug efflux pump, MexXY, from Pseudomonas aeruginosa, Antimicrob. Agents Chemother. 43, 415-417.
83. Chuanchuen, R., Narasaki, C. T., and Schweizer, H. P. (2002) The MexJK efflux pump of Pseudomonas aeruginosa requires OprM for antibiotic efflux but not for efflux of triclosan, J. Bacteriol. 184, 5036-5044.
84. Li, Y., Mima, T., Komori, Y., Morita, Y., Kuroda, T., Mizushima, T., and Tsuchiya, T. (2003) A new member of the tripartite multidrug efflux pumps, MexVW-OprM, in Pseudomonas aeruginosa, J. Antimicrob. Chemother. 52, 572-575.
85. Mima, T., Sekiya, H., Mizushima, T., Kuroda, T., and Tsuchiya, T. (2005) Gene cloning and properties of the RND-type multidrug efflux pumps MexPQ-OpmE and MexMN-OprM from Pseudomonas aeruginosa, Microbiol. Immunol. 49, 999-1002.
86. Aendekerk, S., Diggle, S. P., Song, Z., Hoiby, N., Cornelis, P., Williams, P., and Camara, M. (2005) The MexGHI-OpmD multidrug efflux pump controls growth, antibiotic susceptibility and virulence in Pseudomonas aeruginosa via 4-quinolone-dependent cell-to-cell communication, Microbiology 151, 1113-1125.
87. Morita, Y., Kimura, N., Mima, T., Mizushima, T., and Tsuchiya, T. (2001) Roles of MexXY-and MexAB-multidrug efflux pumps in intrinsic multidrug resistance of Pseudomonas aeruginosa PAO1, J. Gen. Appl. Microbiol. 47, 27-32.
88. Grkovic, S., Brown, M. H., and Skurray, R. A. (2002) Regulation of bacterial drug export systems, Microbiol. Mol. Biol. Rev. 66, 671-701, table of contents.
89. Oh, H., Stenhoff, J., Jalal, S., and Wretlind, B. (2003) 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.
90. Köhler, T., Michea-Hamzehpour, M., Plésiat, P., Kahr, A. L., and Pechere, J. C. (1997) Differential selection of multidrug efflux systems by quinolones in Pseudomonas aeruginosa, Antimicrob. Agents Chemother. 41, 2540-2543.
91. Join-Lambert, O. F., Michea-Hamzehpour, M., Köhler, T., Chau, F., Faurisson, F., Dautrey, S., Vissuzaine, C., Carbon, C., and Pechere, J. (2001) 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.
92. Macia, M. D., Borrell, N., Segura, M., Gomez, C., Perez, J. L., and Oliver, A. (2006) Efficacy and potential for resistance selection of antipseudomonal treatments in a mouse model of lung infection by hypermutable Pseudomonas aeruginosa, Antimicrob. Agents Chemother. 50, 975-983.
93. Cosson, P., Zulianello, L., Join-Lambert, O., Faurisson, F., Gebbie, L., Benghezal, M., Van Delden, C., Curty, L. K., and Köhler, T. (2002) Pseudomonas aeruginosa virulence analyzed in a Dictyostelium discoideum host system, J. Bacteriol. 184, 3027-3033.
94. Sanchez, P., Linares, J. F., Ruiz-Diez, B., Campanario, E., Navas, A., Baquero, F., and Martínez, J. L. (2002) Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants, J. Antimicrob. Chemother. 50, 657-664.
95. Hirakata, Y., Srikumar, R., Poole, K., Gotoh, N., Suematsu, T., Kohno, S., Kamihira, S., Hancock, R. E., and Speert, D. P. (2002) Multidrug efflux systems play an important role in the invasiveness of Pseudomonas aeruginosa, J. Exp. Med. 196, 109-118.
96. Evans, K., Passador, L., Srikumar, R., Tsang, E., Nezezon, J., and Poole, K. (1998) Influence of the MexAB-OprM multidrug efflux system on quorum sensing in Pseudomonas aeruginosa, J. Bacteriol. 180, 5443-5447.
97. Köhler, T., van Delden, C., Curty, L. K., Hamzehpour, M. M., and Pechere, J. C. (2001) Overexpression of the MexEF-OprN multidrug efflux system affects cell-to-cell signaling in Pseudomonas aeruginosa, J. Bacteriol. 183, 5213-5222.
98. Jeannot, K., Elsen, S., Köhler, T., Attree, I., Van Delden, C., and Plésiat, P. (2008) Resistance and virulence of Pseudomonas aeruginosa clinical strains overproducing the MexCD-OprJ efflux pump, Antimicrob. Agents Chemother. 52, 2455-2462.
99. Hocquet, D., Berthelot, P., Roussel-Delvallez, M., Favre, R., Jeannot, K., Bajolet, O., Marty, N., Grattard, F., Mariani-Kurkdjian, P., Bingen, E., et al. (2007) Pseudomonas aeruginosa may accumulate drug resistance mechanisms without losing its ability to cause bloodstream infections, Antimicrob. Agents Chemother. 51, 3531-3536.
100. Ventre, I., Goodman, A. L., Vallet-Gely, I., Vasseur, P., Soscia, C., Molin, S., Bleves, S., Lazdunski, A., Lory, S., and Filloux, A. (2006) Multiple sensors control reciprocal expression of Pseudomonas aeruginosa regulatory RNA and virulence genes, Proc. Natl. Acad. Sci. USA 103, 171-176.
101. Martínez-Solano, L., Macia, M. D., Fajardo, A., Oliver, A., and Martínez, J. L. (2008) Chronic Pseudomonas aeruginosa infection in chronic obstructive pulmonary disease, Clin. Infect. Dis. 47, 1526-1533.
102. Jain, M., Bar-Meir, M., McColley, S., Cullina, J., Potter, E., Powers, C., Prickett, M., Seshadri, R., Jovanovic, B., Petrocheilou, A., et al. (2008) Evolution of Pseudomonas aeruginosa type III secretion in cystic fibrosis: a paradigm of chronic infection, Transl. Res. 152, 257-264.
103. Burke, V., Robinson, J. O., Richardson, C. J., and Bundell, C. S. (1991) Longitudinal studies of virulence factors of Pseudomonas aeruginosa in cystic fibrosis, Pathology 23, 145-148.
104. Linares, J. F., Lopez, J. A., Camafeita, E., Albar, J. P., Rojo, F., and Martínez, J. L. (2005) 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.
105. Vettoretti, L., Plésiat, P., Muller, C., El Garch, F., Phan, G., Attree, I., Ducruix, A., and Llanes, C. (2009) Efflux unbalance in Pseudomonas aeruginosa isolates from cystic fibrosis patients, Antimicrob. Agents Chemother. 53, 1987-1997.
106. Hocquet, D., Muller, A., Blanc, K., Plésiat, P., Talon, D., Monnet, D. L., and Bertrand, X. (2008) Relationship between antibiotic use and incidence of MexXY-OprM overproducers among clinical isolates of Pseudomonas aeruginosa, Antimicrob. Agents Chemother. 52, 1173-1175.
107. Henrichfreise, B., Wiegand, I., Pfister, W., and Wiedemann, B. (2007) Resistance mechanisms of multiresistant Pseudomonas aeruginosa strains from Germany and correlation with hypermutation, Antimicrob. Agents Chemother. 51, 4062-4070.
108. Llanes, C., Neuwirth, C., El Garch, F., Hocquet, D., and Plésiat, P. (2006) Genetic analysis of a multiresistant strain of Pseudomonas aeruginosa producing PER-1 betalactamase, Clin. Microbiol. Infect. 12, 270-278.
109. Rolston, K. V., Kontoyiannis, D. P., Yadegarynia, D., and Raad, II. (2005) Nonfermentative gram-negative bacilli in cancer patients: increasing frequency of infection and antimicrobial susceptibility of clinical isolates to fluoroquinolones, Diagn. Microbiol. Infect. Dis. 51, 215-218.
110. Perz, J. F., Craig, A. S., Stratton, C. W., Bodner, S. J., Phillips, W. E., Jr., and Schaffner, W. (2005) Pseudomonas putida septicemia in a special care nursery due to contaminated flush solutions prepared in a hospital pharmacy, J. Clin. Microbiol. 43, 5316-5318.
111. Teran, W., Felipe, A., Segura, A., Rojas, A., Ramos, J. L., and Gallegos, M. T. (2003) Antibiotic-dependent induction of Pseudomonas putida DOT-T1E TtgABC efflux pump is mediated by the drug binding repressor TtgR, Antimicrob. Agents Chemother. 47, 3067-3072.
112. Noble, R. C., and Overman, S. B. (1994) Pseudomonas stutzeri infection: a review of hospital isolates and a review of the literature, Diagn. Microbiol. Infect. Dis. 19, 51-56.
113. Jude, F., Arpin, C., Brachet-Castang, C., Capdepuy, M., Caumette, P., and Quentin, C. (2004) TbtABM, a multidrug efflux pump associated with tributyltin resistance in Pseudomonas stutzeri, FEMS Microbiol. Lett. 232, 7-14.
114. Ribera, A., Ruiz, J., Jiminez de Anta, M. T., and Vila, J. (2002) Effect of an efflux pump inhibitor on the MIC of nalidixic acid for Acinetobacter baumannii and Stenotrophomonas maltophilia clinical isolates, J. Antimicrob. Chemother. 49, 697-698.
115. Vila, J., Ribera, A., Marco, F., Ruiz, J., Mensa, J., Chaves, J., Hernandez, G., and Jimenez de Anta, M. T. (2002) Activity of clinafloxacin, compared with six other quinolones, against Acinetobacter baumannii clinical isolates, J. Antimicrob. Chemother. 49, 471-477.
116. Fournier, P. E., Vallenet, D., Barbé, V., Audic, S., Ogata, H., Poirel, L., Richet, H., Robert, C., Mangenot, S., Abergel, C., et al. (2006) Comparative genomics of multidrug resistance in Acinetobacter baumannii, PLoS Genet. 2, e7.
117. Damier-Piolle, L., Magnet, S., Bremont, S., Lambert, T., and Courvalin, P. (2008) AdeIJK, a resistance-nodulation-cell division pump effluxing multiple antibiotics in Acinetobacter baumannii, Antimicrob. Agents Chemother. 52, 557-562.
118. Barbé, V., Vallenet, D., Fonknechten, N., Kreimeyer, A., Oztas, S., Labarre, L., Cruveiller, S., Robert, C., Duprat, S., Wincker, P., et al. (2004) Unique features revealed by the genome sequence of Acinetobacter sp. ADP1, a versatile and naturally transformation competent bacterium, Nucleic Acids Res. 32, 5766-5779.
119. Chu, Y. W., Chau, S. L., and Houang, E. T. (2006) Presence of active efflux systems AdeABC, AdeDE and AdeXYZ in different Acinetobacter genomic DNA groups, J. Med. Microbiol. 55, 477-478.
120. Magnet, S., Courvalin, P., and Lambert, T. (2001) Resistance-nodulation-cell divisiontype efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM4454, Antimicrob. Agents Chemother. 45, 3375-3380.
121. Marchand, I., Damier-Piolle, L., Courvalin, P., and Lambert, T. (2004) Expression of the RND-type efflux pump AdeABC in Acinetobacter baumannii is regulated by the AdeRS two-component system, Antimicrob. Agents Chemother. 48, 3298-3304.
122. Nemec, A., Maixnerova, M., van der Reijden, T. J., van den Broek, P. J., and Dijkshoorn, L. (2007) Relationship between the AdeABC efflux system gene content, netilmicin susceptibility and multidrug resistance in a genotypically diverse collection of Acinetobacter baumannii strains, J. Antimicrob. Chemother. 60, 483-489.
123. Chau, S. L., Chu, Y. W., and Houang, E. T. (2004) Novel resistance-nodulation-cell division efflux system AdeDE in Acinetobacter genomic DNA group 3, Antimicrob. Agents Chemother. 48, 4054-4055.
124. Lin, L., Ling, B. D., and Li, X. Z. (2009) Distribution of the multidrug efflux pump genes, adeABC, adeDE and adeIJK, and class 1 integron genes in multiple-antimicrobialresistant clinical isolates of Acinetobacter baumannii-Acinetobacter calcoaceticus complex, Int. J. Antimicrob. Agents 33, 27-32.
125. Su, X. Z., Chen, J., Mizushima, T., Kuroda, T., and Tsuchiya, T. (2005) AbeM, an H + -coupled Acinetobacter baumannii multidrug efflux pump belonging to the MATE family of transporters, Antimicrob. Agents Chemother. 49, 4362-4364.
126. Crossman, L. C., Gould, V. C., Dow, J. M., Vernikos, G. S., Okazaki, A., Sebaihia, M., Saunders, D., Arrowsmith, C., Carver, T., Peters, N., et al. (2008) The complete genome, comparative and functional analysis of Stenotrophomonas maltophilia reveals an organism heavily shielded by drug resistance determinants, Genome Biol. 9, R74.
127. Ryan, R. P., Monchy, S., Cardinale, M., Taghavi, S., Crossman, L., Avison, M. B., Berg, G., van der Lelie, D., and Dow, J. M. (2009) The versatility and adaptation of bacteria from the genus Stenotrophomonas, Nat. Rev. Microbiol. 7, 514-525.
128. Alonso, A., and Martínez, J. L. (1997) Multiple antibiotic resistance in Stenotrophomonas maltophilia, Antimicrob. Agents Chemother. 41, 1140-1142.
129. Alonso, A., and Martínez, J. L. (2000) Cloning and characterization of SmeDEF, a novel multidrug efflux pump from Stenotrophomonas maltophilia, Antimicrob. Agents Chemother. 44, 3079-3086.
130. Alonso, A., and Martínez, J. L. (2001) Expression of multidrug efflux pump SmeDEF by clinical isolates of Stenotrophomonas maltophilia, Antimicrob. Agents Chemother. 45, 1879-1881.
131. Alonso, A., Morales, G., Escalante, R., Campanario, E., Sastre, L., and Martínez, J. L. (2004) Overexpression of the multidrug efflux pump SmeDEF impairs Stenotrophomonas maltophilia physiology, J. Antimicrob. Chemother. 53, 432-434.
132. Zhang, L., Li, X. Z., and Poole, K. (2001) SmeDEF multidrug efflux pump contributes to intrinsic multidrug resistance in Stenotrophomonas maltophilia, Antimicrob. Agents Chemother. 45, 3497-3503.
133. Zhang, L., Li, X. Z., and Poole, K. (2000) Multiple antibiotic resistance in Stenotrophomonas maltophilia: involvement of a multidrug efflux system, Antimicrob. Agents Chemother. 44, 287-293.
134. Li, X. Z., Zhang, L., and Poole, K. (2002) SmeC, an outer membrane multidrug efflux protein of Stenotrophomonas maltophilia, Antimicrob. Agents Chemother. 46, 333-343.
135. Sanchez, P., Alonso, A., and Martínez, J. L. (2002) Cloning and characterization of SmeT, a repressor of the Stenotrophomonas maltophilia multidrug efflux pump Sme-DEF, Antimicrob. Agents Chemother. 46, 3386-3393.
136. Hernández, A., Mate, M. J., Sanchez-Diaz, P. C., Romero, A., Rojo, F., andMartínez, J. L. (2009) Structural and functional analysis of SmeT, the repressor of the Stenotrophomonas maltophilia multidrug efflux pump SmeDEF, J. Biol. Chem. 284, 14428-14438.
137. Sanchez, P., Alonso, A., and Martínez, J. L. (2004) Regulatory regions of smeDEF in Stenotrophomonas maltophilia strains expressing different amounts of the multidrug efflux pump SmeDEF, Antimicrob. Agents Chemother. 48, 2274-2276.
138. Ribera, A., Domenech-Sanchez, A., Ruiz, J., Benedi, V. J., Jimenez de Anta, M. T., and Vila, J. (2002) Mutations in gyrA and parC QRDRs are not relevant for quinolone resistance in epidemiological unrelated Stenotrophomonas maltophilia clinical isolates, Microb. Drug Resist. 8, 245-251.
139. Valdezate, S., Vindel, A., Saez-Nieto, J. A., Baquero, F., and Canton, R. (2005) Preservation of topoisomerase genetic sequences during in vivo and in vitro development of high-level resistance to ciprofloxacin in isogenic Stenotrophomonas maltophilia strains, J. Antimicrob. Chemother. 56, 220-223.
140. Sánchez, M. B., Hernández, A., Rodríguez-Martínez, J. M., Martínez-Martínez, L., and Martínez, J. L. (2008) Predictive analysis of transmissible quinolone resistance indicates Stenotrophomonas maltophilia as a potential source of a novel family of Qnr determinants, BMC Microbiol. 8, 148.
141. Shimizu, K., Kikuchi, K., Sasaki, T., Takahashi, N., Ohtsuka, M., Ono, Y., andHiramatsu, K. (2008) Smqnr, a newchromosome-carried quinolone resistance gene in Stenotrophomonas maltophilia, Antimicrob. Agents Chemother. 52, 3823-3825.
142. Jacoby, G., Cattoir, V., Hooper, D., Martínez-Martínez, L., Nordmann, P., Pascual, A., Poirel, L., and Wang, M. (2008) qnr Gene nomenclature, Antimicrob. Agents Chemother. 52, 2297-2299.
143. Martínez-Martínez, L., Pascual, A., and Jacoby, G. A. (1998) Quinolone resistance from a transferable plasmid, Lancet 351, 797-799.
144. Sanchez, P., Moreno, E., and Martínez, J. L. (2005) The biocide triclosan selects Stenotrophomonas maltophilia mutants that overproduce the SmeDEF multidrug efflux pump, Antimicrob. Agents Chemother. 49, 781-782.
145. Valvano, M. A., Keith, K. E., and Cardona, S. T. (2005) Survival and persistence of opportunistic Burkholderia species in host cells, Curr. Opin. Microbiol. 8, 99-105.
146. Holden, M. T., Titball, R. W., Peacock, S. J., Cerdeno-Tarraga, A. M., Atkins, T., Crossman, L. C., Pitt, T., Churcher, C., Mungall, K., Bentley, S. D., et al. (2004) Genomic plasticity of the causative agent of melioidosis, Burkholderia pseudomallei, Proc. Natl. Acad. Sci. USA 101, 14240-14245.
147. Kumar, A., Mayo, M., Trunck, L. A., Cheng, A. C., Currie, B. J., and Schweizer, H. P. (2008) Expression of resistance-nodulation-cell-division efflux pumps in commonly used Burkholderia pseudomallei strains and clinical isolates from northern Australia, Trans. R. Soc. Trop. Med. Hyg. 102(Suppl. 1), S145-S151.
148. Chan, Y. Y., Tan, T. M., Ong, Y. M., and Chua, K. L. (2004) BpeAB-OprB, a multidrug efflux pump in Burkholderia pseudomallei, Antimicrob. Agents Chemother. 48, 1128-1135.
149. Kumar, A., Chua, K. L., and Schweizer, H. P. (2006) Method for regulated expression of single-copy efflux pump genes in a surrogate Pseudomonas aeruginosa strain: identification of the BpeEF-OprC chloramphenicol and trimethoprim efflux pump of Burkholderia pseudomallei 1026b, Antimicrob. Agents Chemother. 50, 3460-3463.
150. Chan, Y. Y., Ong, Y. M., and Chua, K. L. (2007) Synergistic interaction between phenothiazines and antimicrobial agents against Burkholderia pseudomallei, Antimicrob. Agents Chemother. 51, 623-630.
151. Guglierame, P., Pasca, M. R., De Rossi, E., Buroni, S., Arrigo, P., Manina, G., and Riccardi, G. (2006) Efflux pump genes of the resistance-nodulation-division family in Burkholderia cenocepacia genome, BMC Microbiol. 6, 66.
152. Wigfield, S. M., Rigg, G. P., Kavari, M., Webb, A. K., Matthews, R. C., and Burnie, J. P. (2002) Identification of an immunodominant drug efflux pump in Burkholderia cepacia, J. Antimicrob. Chemother. 49, 619-624.
153. Piddock, L. J. (2006) Multidrug-resistance efflux pumps-not just for resistance, Nat. Rev. Microbiol. 4, 629-636.
154. Andriole, V. T. (2005) The quinolones: past, present, and future, Clin. Infect. Dis. 41 (Suppl. 2), S113-S119.
155. Yoshida, H., Bogaki, M., Nakamura, S., Ubukata, K., and Konno, M. (1990) Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones, J. Bacteriol. 172, 6942-6949.
156. Gill, M. J., Brenwald, N. P., and Wise, R. (1999) Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae, Antimicrob. Agents Chemother. 43, 187-189.
157. Neyfakh, A. A. (1992) The multidrug efflux transporter of Bacillus subtilis is a structural and functional homolog of the Staphylococcus NorA protein, Antimicrob. Agents Chemother. 36, 484-485.
158. Neyfakh, A. A., Borsch, C. M., and Kaatz, G. W. (1993) Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter, Antimicrob. Agents Chemother. 37, 128-129.
159. Ng, E. Y., Trucksis, M., and Hooper, D. C. (1994) 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.
160. Kaatz, G. W., Thyagarajan, R. V., and Seo, S. M. (2005) Effect of promoter region mutations and mgrA overexpression on transcription of norA, which encodes a Staphylococcus aureus multidrug efflux transporter, Antimicrob. Agents Chemother. 49, 161-169.
161. Fournier, B., Aras, R., and Hooper, D. C. (2000) Expression of the multidrug resistance transporter NorA from Staphylococcus aureus is modified by a two-component regulatory system, J. Bacteriol. 182, 664-671.
162. Fournier, B., and Hooper, D. C. (2000) A new two-component regulatory system involved in adhesion, autolysis, and extracellular proteolytic activity of Staphylococcus aureus, J. Bacteriol. 182, 3955-3964.
163. Truong-Bolduc, Q. C., Zhang, X., and Hooper, D. C. (2003) Characterization of NorR protein, a multifunctional regulator of norA expression in Staphylococcus aureus, J. Bacteriol. 185, 3127-3138.
164. Luong, T. T., Newell, S. W., and Lee, C. Y. (2003) Mgr, a novel global regulator in Staphylococcus aureus, J. Bacteriol. 185, 3703-3710.
165. Truong-Bolduc, Q. C., and Hooper, D. C. (2007) The transcriptional regulators NorG and MgrA modulate resistance to both quinolones and beta-lactams in Staphylococcus aureus, J. Bacteriol. 189, 2996-3005.
166. Noguchi, N., Tamura, M., Narui, K., Wakasugi, K., and Sasatsu, M. (2002) Frequency and genetic characterization of multidrug-resistant mutants of Staphylococcus aureus after selection with individual antiseptics and fluoroquinolones, Biol. Pharm. Bull. 25, 1129-1132.
167. Kaatz, G. W., Moudgal, V. V., and Seo, S. M. (2002) Identification and characterization of a novel efflux-related multidrug resistance phenotype in Staphylococcus aureus, J. Antimicrob. Chemother. 50, 833-838.
168. Truong-Bolduc, Q. C., Dunman, P. M., Strahilevitz, J., Projan, S. J., and Hooper, D. C. (2005) MgrA is a multiple regulator of two new efflux pumps in Staphylococcus aureus, J. Bacteriol. 187, 2395-2405.
169. Truong-Bolduc, Q. C., Strahilevitz, J., and Hooper, D. C. (2006) NorC, a new efflux pump regulated by MgrA of Staphylococcus aureus, Antimicrob. Agents Chemother. 50, 1104-1107.
170. Yamada, Y., Hideka, K., Shiota, S., Kuroda, T., and Tsuchiya, T. (2006) Gene cloning and characterization of SdrM, a chromosomally-encoded multidrug efflux pump, from Staphylococcus aureus, Biol. Pharm. Bull. 29, 554-556.
171. Yamada, Y., Shiota, S., Mizushima, T., Kuroda, T., and Tsuchiya, T. (2006) Functional gene cloning and characterization of MdeA, a multidrug efflux pump from Staphylococcus aureus, Biol. Pharm. Bull. 29, 801-804.
172. Huang, J., O'Toole, P.W., Shen, W., Amrine-Madsen, H., Jiang, X., Lobo, N., Palmer, L. M., Voelker, L., Fan, F., Gwynn, M. N., and McDevitt, D. (2004) Novel chromosomally encoded multidrug efflux transporter MdeA in Staphylococcus aureus, Antimicrob. Agents Chemother. 48, 909-917.
173. McAleese, F., Petersen, P., Ruzin, A., Dunman, P. M., Murphy, E., Projan, S. J., and Bradford, P. A. (2005) A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline, Antimicrob. Agents Chemother. 49, 1865-1871.
174. Kaatz, G. W., McAleese, F., and Seo, S. M. (2005) Multidrug resistance in Staphylococcus aureus due to overexpression of a novel multidrug and toxin extrusion (MATE) transport protein, Antimicrob. Agents Chemother. 49, 1857-1864.
175. Kaatz, G. W., DeMarco, C. E., and Seo, S. M. (2006) MepR, a repressor of the Staphylococcus aureus MATE family multidrug efflux pump MepA, is a substrateresponsive regulatory protein, Antimicrob. Agents Chemother. 50, 1276-1281.
176. DeMarco, C.E., Cushing, L.A., Frempong-Manso, E., Seo, S.M., Jaravaza, T.A., andKaatz, G. W. (2007) Efflux-related resistance to norfloxacin, dyes, and biocides in bloodstream isolates of Staphylococcus aureus, Antimicrob. Agents Chemother. 51, 3235-3239.
177. Piddock, L. J., Johnson, M. M., Simjee, S., and Pumbwe, L. (2002) Expression of efflux pump gene pmrA in fluoroquinolone-resistant and -susceptible clinical isolates of Streptococcus pneumoniae, Antimicrob. Agents Chemother. 46, 808-812.
178. Martinez-Garriga, B., Vinuesa, T., Hernandez-Borrell, J., and Vinas, M. (2007) The contribution of efflux pumps to quinolone resistance in Streptococcus pneumoniae clinical isolates, Int. J. Med. Microbiol. 297, 187-195.
179. Robertson, G. T., Doyle, T. B., and Lynch, A. S. (2005) Use of an efflux-deficient Streptococcus pneumoniae strain panel to identify ABC-class multidrug transporters involved in intrinsic resistance to antimicrobial agents, Antimicrob. Agents Chemother. 49, 4781-4783.
180. Brenwald, N. P., Appelbaum, P., Davies, T., and Gill, M. J. (2003) Evidence for efflux pumps, other than PmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae, Clin. Microbiol. Infect. 9, 140-143.
181. Pestova, E., Millichap, J. J., Siddiqui, F., Noskin, G. A., and Peterson, L. R. (2002) Non-PmrA-mediated multidrug resistance in Streptococcus pneumoniae, J. Antimicrob. Chemother. 49, 553-556.
182. Marrer, E., Satoh, A. T., Johnson, M. M., Piddock, L. J., and Page, M. G. (2006) Global transcriptome analysis of the responses of a fluoroquinolone-resistant Streptococcus pneumoniae mutant and its parent to ciprofloxacin, Antimicrob. Agents Chemother. 50, 269-278.
183. Garvey, M. I., and Piddock, L. J. (2008) The efflux pump inhibitor reserpine selects multidrug-resistant Streptococcus pneumoniae strains that overexpress the ABC transporters PatA and PatB, Antimicrob. Agents Chemother. 52, 1677-1685.
184. Marrer, E., Schad, K., Satoh, A. T., Page, M. G., Johnson, M. M., and Piddock, L. J. (2006) 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.
185. Avrain, L., Garvey, M., Mesaros, N., Glupczynski, Y., Mingeot-Leclercq, M. P., Piddock, L. J., Tulkens, P. M., Vanhoof, R., and Van Bambeke, F. (2007) Selection of quinolone resistance in Streptococcus pneumoniae exposed in vitro to subinhibitory drug concentrations, J. Antimicrob. Chemother. 60, 965-972.
186. Jones, H. E., Brenwald, N. P., Owen, K. A., and Gill, M. J. (2003) A multidrug efflux phenotype mutant of Streptococcus pyogenes, J. Antimicrob. Chemother. 51, 707-710.
187. Leclercq, R. (2009) Epidemiological and resistance issues in multidrug-resistant staphylococci and enterococci, Clin. Microbiol. Infect. 15, 224-231.
188. Witte, W., Cuny, C., Klare, I., Nubel, U., Strommenger, B., and Werner, G. (2008) Emergence and spread of antibiotic-resistant gram-positive bacterial pathogens, Int. J. Med. Microbiol. 298, 365-377.
189. Top, J., Willems, R., and Bonten, M. (2008) Emergence of CC17 Enterococcus faecium: from commensal to hospital-adapted pathogen, FEMS Immunol. Med. Microbiol. 52, 297-308.
190. Arsene, S., and Leclercq, R. (2007) Role of a qnr-like gene in the intrinsic resistance of Enterococcus faecalis to fluoroquinolones, Antimicrob. AgentsChemother. 51, 3254-3258.
191. Jonas, B. M., Murray, B. E., and Weinstock, G. M. (2001) Characterization of emeA, a NorA homolog and multidrug resistance efflux pump, in Enterococcus faecalis, Antimicrob. Agents Chemother. 45, 3574-3579.
192. Lee, E. W., Chen, J., Huda, M. N., Kuroda, T., Mizushima, T., and Tsuchiya, T. (2003) Functional cloning and expression of emeA, and characterization of EmeA, a multidrug efflux pump from Enterococcus faecalis, Biol. Pharm. Bull. 26, 266-270.
193. Lee, E. W., Huda, M. N., Kuroda, T., Mizushima, T., and Tsuchiya, T. (2003) EfrAB, an ABC multidrug efflux pump in Enterococcus faecalis, Antimicrob. Agents Chemother. 47, 3733-3738.
194. Oyamada, Y., Ito, H., Fujimoto, K., Asada, R., Niga, T., Okamoto, R., Inoue, M., and Yamagishi, J. (2006) Combination of known and unknown mechanisms confers highlevel resistance to fluoroquinolones in Enterococcus faecium, J. Med. Microbiol. 55, 729-736.
195. Nishioka, T., Ogawa, W., Kuroda, T., Katsu, T., and Tsuchiya, T. (2009) Gene cloning and characterization of EfmA, a multidrug efflux pump, from Enterococcus faecium, Biol. Pharm. Bull. 32, 483-488.
196. Ahmed, M., Borsch, C. M., Taylor, S. S., Vazquez-Laslop, N., and Neyfakh, A. A. (1994) A protein that activates expression of a multidrug efflux transporter upon binding the transporter substrates, J. Biol. Chem. 269, 28506-28513.
197. Ahmed, M., Lyass, L., Markham, P. N., Taylor, S. S., Vazquez-Laslop, N., and Neyfakh, A. A. (1995) Two highly similar multidrug transporters of Bacillus subtilis whose expression is differentially regulated, J. Bacteriol. 177, 3904-3910.
198. Holmes, D. J., Caso, J. L., and Thompson, C. J. (1993) Autogenous transcriptional activation of a thiostrepton-induced gene in Streptomyces lividans, EMBO J. 12, 3183-3191.
199. Summers, A. O. (1992) Untwist and shout: a heavy metal-responsive transcriptional regulator, J. Bacteriol. 174, 3097-3101.
200. Baranova, N. N., Danchin, A., and Neyfakh, A. A. (1999) Mta, a global MerR-type regulator of the Bacillus subtilis multidrug-efflux transporters, Mol. Microbiol. 31, 1549-1559.
201. Ohki, R., and Murata, M. (1997) bmr3, a third multidrug transporter gene of Bacillus subtilis, J. Bacteriol. 179, 1423-1427.
202. Ohki, R., and Tateno, K. (2004) Increased stability of bmr3 mRNA results in a multidrugresistant phenotype in Bacillus subtilis, J. Bacteriol. 186, 7450-7455.
203. Godreuil, S., Galimand, M., Gerbaud, G., Jacquet, C., and Courvalin, P. (2003) Efflux pump Lde is associated with fluoroquinolone resistance in Listeria monocytogenes, Antimicrob. Agents Chemother. 47, 704-708.
204. Rautelin, H., and Hanninen, M. L. (2000) Campylobacters: the most common bacterial enteropathogens in the Nordic countries, Ann. Med. 32, 440-445.
205. Hanninen, M. L., and Hannula, M. (2007) Spontaneous mutation frequency and emergence of ciprofloxacin resistance in Campylobacter jejuni and Campylobacter coli, J. Antimicrob. Chemother. 60, 1251-1257.
206. Luo, N., Sahin, O., Lin, J., Michel, L. O., and Zhang, Q. (2003) In vivo selection of Campylobacter isolates with high levels of fluoroquinolone resistance associated with gyrA mutations and the function of the CmeABC efflux pump, Antimicrob. Agents Chemother. 47, 390-394.
207. Ge, B., McDermott, P. F., White, D. G., and Meng, J. (2005) Role of efflux pumps and topoisomerase mutations in fluoroquinolone resistance in Campylobacter jejuni and Campylobacter coli, Antimicrob. Agents Chemother. 49, 3347-3354.
208. Lin, J., Michel, L. O., and Zhang, Q. (2002) CmeABC functions as a multidrug efflux system in Campylobacter jejuni, Antimicrob. Agents Chemother. 46, 2124-2131.
209. Lin, J., Akiba, M., Sahin, O., and Zhang, Q. (2005) CmeR functions as a transcriptional repressor for the multidrug efflux pump CmeABC in Campylobacter jejuni, Antimicrob. Agents Chemother. 49, 1067-1075.
210. Rafii, F., Park, M., and Wynne, R. (2005) Evidence for active drug efflux in fluoroquinolone resistance in Clostridium hathewayi, Chemotherapy 51, 256-262.
211. Perez-Vazquez, M., Roman, F., Garcia-Cobos, S., and Campos, J. (2007) Fluoroquinolone resistance in Haemophilus influenzae is associated with hypermutability, Antimicrob. Agents Chemother. 51, 1566-1569.
212. Xu, X. J., Su, X. Z., Morita, Y., Kuroda, T., Mizushima, T., and Tsuchiya, T. (2003) Molecular cloning and characterization of the HmrM multidrug efflux pump from Haemophilus influenzae Rd, Microbiol. Immunol. 47, 937-943.
213. Singh, A. K., Haldar, R., Mandal, D., and Kundu, M. (2006) Analysis of the topology of Vibrio cholerae NorM and identification of amino acid residues involved in norfloxacin resistance, Antimicrob. Agents Chemother. 50, 3717-3723.
214. Giraud, E., Blanc, G., Bouju-Albert, A., Weill, F. X., and Donnay-Moreno, C. (2004) Mechanisms of quinolone resistance and clonal relationship among Aeromonas salmonicida strains isolated from reared fish with furunculosis, J. Med. Microbiol. 53, 895-901.
215. Jacobs, L., and Chenia, H. Y. (2007) Characterization of integrons and tetracycline resistance determinants in Aeromonas spp. isolated from South African aquaculture systems, Int. J. Food Microbiol. 114, 295-306.
216. Sánchez-Céspedes, J., Blasco, M. D., Marti, S., Alba, V., Alcalde, E., Esteve, C., and Vila, J. (2008) Plasmid-mediated QnrS2 determinant from a clinical Aeromonas veronii isolate, Antimicrob. Agents Chemother. 52, 2990-2991.
217. Kuroda, T., and Tsuchiya, T. (2009) Multidrug efflux transporters in the MATE family, Biochim. Biophys. Acta 1794, 763-768.
218. Colmer, J. A., Fralick, J. A., and Hamood, A. N. (1998) Isolation and characterization of a putative multidrug resistance pump from Vibrio cholerae, Mol. Microbiol. 27, 63-72.
219. Woolley, R. C., Vediyappan, G., Anderson, M., Lackey, M., Ramasubramanian, B., Jiangping, B., Borisova, T., Colmer, J. A., Hamood, A. N., McVay, C. S., and Fralick, J. A. (2005) Characterization of the Vibrio cholerae vceCAB multiple-drug resistance efflux operon in Escherichia coli, J. Bacteriol. 187, 5500-5503.
220. Huda, N., Lee, E. W., Chen, J., Morita, Y., Kuroda, T., Mizushima, T., and Tsuchiya, T. (2003) Molecular cloning and characterization of an ABC multidrug efflux pump, VcaM, in Non-O1 Vibrio cholerae, Antimicrob. Agents Chemother. 47, 2413-2417.
221. Morita, Y., Kodama, K., Shiota, S., Mine, T., Kataoka, A., Mizushima, T., and Tsuchiya, T. (1998) NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli, Antimicrob. Agents Chemother. 42, 1778-1782.
222. Brown, M. H., Paulsen, I. T., and Skurray, R. A. (1999) The multidrug efflux protein NorM is a prototype of a new family of transporters, Mol. Microbiol. 31, 394-395.
223. Morita, Y., Kataoka, A., Shiota, S., Mizushima, T., and Tsuchiya, T. (2000) NorM of Vibrio parahaemolyticus is an Na(+)-driven multidrug efflux pump, J. Bacteriol. 182, 6694-6697.
224. Wexler, H.M. (2007) Bacteroides: the good, the bad, and the nitty-gritty, Clin. Microbiol. Rev. 20, 593-621.
225. Ueda, O., Wexler, H. M., Hirai, K., Shibata, Y., Yoshimura, F., and Fujimura, S. (2005) Sixteen homologs of the mex-type multidrug resistance efflux pump in Bacteroides fragilis, Antimicrob. Agents Chemother. 49, 2807-2815.
226. Pumbwe, L., Ueda, O., Yoshimura, F., Chang, A., Smith, R. L., andWexler, H.M. (2006) Bacteroides fragilis BmeABC efflux systems additively confer intrinsic antimicrobial resistance, J. Antimicrob. Chemother. 58, 37-46.
227. Pumbwe, L., Chang, A., Smith, R. L., and Wexler, H. M. (2006) Clinical significance of overexpression of multiple RND-family efflux pumps in Bacteroides fragilis isolates, J. Antimicrob. Chemother. 58, 543-548.
228. Miyamae, S., Nikaido, H., Tanaka, Y., and Yoshimura, F. (1998) Active efflux of norfloxacin by Bacteroides fragilis, Antimicrob. Agents Chemother. 42, 2119-2121.
229. Miyamae, S., Ueda, O., Yoshimura, F., Hwang, J., Tanaka, Y., and Nikaido, H. (2001) A MATE family multidrug efflux transporter pumps out fluoroquinolones in Bacteroides thetaiotaomicron, Antimicrob. Agents Chemother. 45, 3341-3346.
230. Ikeda, T., and Yoshimura, F. (2002) A resistance-nodulation-cell division family xenobiotic efflux pump in an obligate anaerobe, Porphyromonas gingivalis, Antimicrob. Agents Chemother. 46, 3257-3260.
231. Dridi, L., Tankovic, J., and Petit, J. C. (2004) CdeA of Clostridium difficile, a new multidrug efflux transporter of the MATE family, Microb. Drug Resist. 10, 191-196.
232. Rafii, F., and Park, M. (2008) Detection and characterization of an ABC transporter in Clostridium hathewayi, Arch. Microbiol. 190, 417-426.
233. Liu, J., Takiff, H. E., and Nikaido, H. (1996) Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump, J. Bacteriol. 178, 3791-3795.
234. Takiff, H. E., Cimino, M., Musso, M. C., Weisbrod, T., Martinez, R., Delgado, M. B., Salazar, L., Bloom, B. R., and Jacobs, W. R., Jr., (1996) Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis, Proc. Natl. Acad. Sci. USA 93, 362-366.
235. Li, X. Z., Zhang, L., and Nikaido, H. (2004) Efflux pump-mediated intrinsic drug resistance in Mycobacterium smegmatis, Antimicrob. Agents Chemother. 48, 2415-2423.
236. Sander, P., De Rossi, E., Boddinghaus, B., Cantoni, R., Branzoni, M., Bottger, E. C., Takiff, H., Rodriquez, R., Lopez, G., and Riccardi, G. (2000) Contribution of the multidrug efflux pump LfrA to innate mycobacterial drug resistance, FEMS Microbiol. Lett. 193, 19-23.
237. Buroni, S., Manina, G., Guglierame, P., Pasca, M. R., Riccardi, G., and De Rossi, E. (2006) LfrR is a repressor that regulates expression of the efflux pump LfrA in Mycobacterium smegmatis, Antimicrob. Agents Chemother. 50, 4044-4052.
238. De Rossi, E., Arrigo, P., Bellinzoni, M., Silva, P. A., Martin, C., Ainsa, J. A., Guglierame, P., and Riccardi, G. (2002) The multidrug transporters belonging to major facilitator superfamily in Mycobacterium tuberculosis, Mol. Med. 8, 714-724.
239. Bhatt, K., Banerjee, S. K., and Chakraborti, P. K. (2000) Evidence that phosphate specific transporter is amplified in a fluoroquinolone resistant Mycobacterium smegmatis, Eur. J. Biochem. 267, 4028-4032.
240. Banerjee, S. K., Bhatt, K., Misra, P., and Chakraborti, P. K. (2000) Involvement of a natural transport system in the process of efflux-mediated drug resistance in Mycobacterium smegmatis, Mol. Gen. Genet. 262, 949-956.
241. Pasca, M. R., Guglierame, P., Arcesi, F., Bellinzoni, M., De Rossi, E., and Riccardi, G. (2004) Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis, Antimicrob. Agents Chemother. 48, 3175-3178.
242. Courvalin, P. (1990) Plasmid-mediated 4-quinolone resistance: a real or apparent absence? Antimicrob. Agents Chemother. 34, 681-684.
243. Gomez-Gomez, J. M., Blazquez, J., Espinosa De Los Monteros, L. E., Baquero, M. R., Baquero, F., and Martínez, J. L. (1997) In vitro plasmid-encoded resistance to quinolones, FEMS Microbiol. Lett. 154, 271-276.
244. Martínez, J. L., Alonso, A., Gomez-Gomez, J. M., and Baquero, F. (1998) Quinolone resistance by mutations in chromosomal gyrase genes: Just the tip of the iceberg? J. Antimicrob. Chemother. 42, 683-688.
245. Robicsek, A., Strahilevitz, J., Jacoby, G. A., Macielag, M., Abbanat, D., Park, C. H., Bush, K., and Hooper, D. C. (2006) Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase, Nat. Med. 12, 83-88.
246. Yamane, K., Wachino, J., Suzuki, S., Kimura, K., Shibata, N., Kato, H., Shibayama, K., Konda, T., and Arakawa, Y. (2007) New plasmid-mediated fluoroquinolone efflux pump, QepA, found in an Escherichia coli clinical isolate, Antimicrob. Agents Chemother. 51, 3354-3360.
247. Kim, H. B., Park, C. H., Kim, C. J., Kim, E. C., Jacoby, G. A., and Hooper, D. C. (2009) Prevalence of plasmid-mediated quinolone resistance determinants over a 9-year period, Antimicrob. Agents Chemother. 53, 639-645.
248. Yamane, K., Wachino, J., Suzuki, S., and Arakawa, Y. (2008) Plasmid-mediated qepA gene among Escherichia coli clinical isolates from Japan, Antimicrob. Agents Chemother. 52, 1564-1566.
249. Liu, J. H., Deng, Y. T., Zeng, Z. L., Gao, J. H., Chen, L., Arakawa, Y., and Chen, Z. L. (2008) Coprevalence of plasmid-mediated quinolone resistance determinants QepA, Qnr, and AAC(60)-Ib-cr among 16S rRNA methylase RmtB-producing Escherichia coli isolates from pigs, Antimicrob. Agents Chemother. 52, 2992-2993.
250. Ma, J., Zeng, Z., Chen, Z., Xu, X., Wang, X., Deng, Y., Lu, D., Huang, L., Zhang, Y., Liu, J., and Wang, M. (2009) High prevalence of plasmid-mediated quinolone resistance determinants qnr, aac(60)-Ib-cr, and qepA among ceftiofur-resistant Enterobacteriaceae isolates from companion and food-producing animals, Antimicrob. Agents Chemother. 53, 519-524.
251. Martínez, J. L. (2009) The role of natural environments in the evolution of resistance traits in pathogenic bacteria, Proc. Biol. Sci. 276, 2521-2530.
252. Perichon, B., Courvalin, P., and Galimand, M. (2007) Transferable resistance to aminoglycosides by methylation of G1405 in 16S rRNA and to hydrophilic fluoroquinolones by QepA-mediated efflux in Escherichia coli, Antimicrob. Agents Chemother. 51, 2464-2469.
253. Cattoir, V., Poirel, L., and Nordmann, P. (2008) Plasmid-mediated quinolone resistance pump QepA2 in an Escherichia coli isolate from France, Antimicrob. Agents Chemother. 52, 3801-3804.
254. Hansen, L. H., Johannesen, E., Burmolle, M., Sorensen, A. H., and Sorensen, S. J. (2004) Plasmid-encoded multidrug efflux pump conferring resistance to olaquindox in Escherichia coli, Antimicrob. Agents Chemother. 48, 3332-3337.
255. Hansen, L. H., Jensen, L. B., Sorensen, H. I., and Sorensen, S. J. (2007) Substrate specificity of the OqxAB multidrug resistance pump in Escherichia coli and selected enteric bacteria, J. Antimicrob. Chemother. 60, 145-147.
256. Hansen, L. H., Sorensen, S. J., Jorgensen, H. S., and Jensen, L. B. (2005) The prevalence of the OqxAB multidrug efflux pump amongst olaquindox-resistant Escherichia coli in pigs, Microb. Drug Resist. 11, 378-382.
257. Kim, H. B., Wang, M., Park, C. H., Kim, E. C., Jacoby, G. A., and Hooper, D. C. (2009) oqxAB encoding a multidrug efflux pump in human clinical isolates of Enterobacteriaceae, Antimicrob. Agents Chemother. 53, 3582-3584.
258. Vila, J., and Martínez, J. L. (2008) Clinical impact of the over-expression of efflux pump in nonfermentative gram-negative bacilli, development of efflux pump inhibitors, Curr. Drug Targets 9, 797-807.
259. Zhang, L., and Mah, T. F. (2008) Involvement of a novel efflux system in biofilm-specific resistance to antibiotics, J. Bacteriol. 190, 4447-4452.
260. Ruzin, A., Keeney, D., and Bradford, P. A. (2007) AdeABC multidrug efflux pump is associated with decreased susceptibility to tigecycline in Acinetobacter calcoaceticus-Acinetobacter baumannii complex, J. Antimicrob. Chemother. 59, 1001-1004.
261. Viktorov, D. V., Zakharova, I. B., Podshivalova, M. V., Kalinkina, E. V., Merinova, O. A., Ageeva, N. P., Antonov, V. A., Merinova, L. K., and Alekseev, V. V. (2008) High-level resistance to fluoroquinolones and cephalosporins in Burkholderia pseudomallei and closely related species, Trans. R. Soc. Trop. Med. Hyg. 102(Suppl. 1), S103-S110.
262. Poole, K. (2004) Efflux-mediated multiresistance in gram-negative bacteria, Clin. Microbiol. Infect. 10, 12-26.
263. Middlemiss, J. K., and Poole, K. (2004) Differential impact of MexB mutations on substrate selectivity of the MexAB-OprM multidrug efflux pump of Pseudomonas aeruginosa, J. Bacteriol. 186, 1258-1269.
264. He, G. X., Kuroda, T., Mima, T., Morita, Y., Mizushima, T., and Tsuchiya, T. (2004) An H(+)-coupled multidrug efflux pump, PmpM, a member of the MATE family of transporters, from Pseudomonas aeruginosa, J. Bacteriol. 186, 262-265.
265. Hearn, E. M., Dennis, J. J., Gray, M. R., and Foght, J. M. (2003) Identification and characterization of the emhABC efflux system for polycyclic aromatic hydrocarbons in Pseudomonas fluorescens cLP6a, J. Bacteriol. 185, 6233-6240.
266. Hearn, E. M., Gray, M. R., and Foght, J. M. (2006) Mutations in the central cavity and periplasmic domain affect efflux activity of the resistance-nodulation-division pump EmhB from Pseudomonas fluorescens cLP6a, J. Bacteriol. 188, 115-123.
267. Duque, E., Segura, A., Mosqueda, G., and Ramos, J. L. (2001) Global and cognate regulators control the expression of the organic solvent efflux pumps TtgABC and TtgDEF of Pseudomonas putida, Mol. Microbiol. 39, 1100-1106.
268. Huda, M. N., Morita, Y., Kuroda, T., Mizushima, T., and Tsuchiya, T. (2001) Na + -driven multidrug efflux pump VcmA from Vibrio cholerae non-O1, a non-halophilic bacterium, FEMS Microbiol. Lett. 203, 235-239.
269. Begum, A., Rahman, M. M., Ogawa, W., Mizushima, T., Kuroda, T., and Tsuchiya, T. (2005) Gene cloning and characterization of four MATE family multidrug efflux pumps from Vibrio cholerae non-O1, Microbiol. Immunol. 49, 949-957.