, Volume 64, Issue 2, pp 159–204 | Cite as

Efflux-Mediated Drug Resistance in Bacteria

  • Xian-Zhi Li
  • Hiroshi NikaidoEmail author
Review Article


Drug resistance in bacteria, and especially resistance to multiple antibacterials, has attracted much attention in recent years. In addition to the well known mechanisms, such as inactivation of drugs and alteration of targets, active efflux is now known to play a major role in the resistance of many species to antibacterials. Drug-specific efflux (e.g. that of tetracycline) has been recognised as the major mechanism of resistance to this drug in Gram-negative bacteria. In addition, we now recognise that multidrug efflux pumps are becoming increasingly important. Such pumps play major roles in the antiseptic resistance of Staphylococcus aureus, and fluoroquinolone resistance of S. aureus and Streptococcus pneumoniae. Multidrug pumps, often with very wide substrate specificity, are not only essential for the intrinsic resistance of many Gram-negative bacteria but also produce elevated levels of resistance when overexpressed. Paradoxically, ‘advanced’ agents for which resistance is unlikely to be caused by traditional mechanisms, such as fluoroquinolones and β-lactams of the latest generations, are likely to select for overproduction mutants of these pumps and make the bacteria resistant in one step to practically all classes of antibacterial agents. Such overproduction mutants are also selected for by the use of antiseptics and biocides, increasingly incorporated into consumer products, and this is also of major concern. We can consider efflux pumps as potentially effective antibacterial targets. Inhibition of efflux pumps by an efflux pump inhibitor would restore the activity of an agent subject to efflux. An alternative approach is to develop antibacterials that would bypass the action of efflux pumps.



Research in the authors’ laboratory was supported by a grant from the US Public Health Service (AI-09644). A portion of the review is based on the PhD thesis of X.-Z. Li, who thanks Keith Poole for his encouragement during the graduate study in his laboratory. Neither author has any disclosable interest relevant to the content of the review.


  1. 1.
    Levy SB. Antibiotic resistance: an ecological imbalance. Ciba Found Symp 1997; 207: 1–9PubMedGoogle Scholar
  2. 2.
    Normark BH, Normark S. Evolution and spread of antibiotic resistance. J Intern Med 2002 Aug; 252(2): 91–106PubMedCrossRefGoogle Scholar
  3. 3.
    Ball PR, Chopra I, Eccles SJ. Accumulation of tetracyclines by Escherichia coli K-12. Biochem Biophys Res Commun 1977 Aug 22; 77(4): 1500–7PubMedCrossRefGoogle Scholar
  4. 4.
    Ball PR, Shales SW, Chopra I. Plasmid-mediated tetracycline resistance in Escherichia coli involves increased efflux of the antibiotic. Biochem Biophys Res Commun 1980 Mar 13; 93(1): 74–81PubMedCrossRefGoogle Scholar
  5. 5.
    Levy SB, McMurry L. Plasmid-determined tetracycline resistance involves new transport systems for tetracycline. Nature 1978 Nov 2; 276(5683): 90–2PubMedCrossRefGoogle Scholar
  6. 6.
    McMurry L, Petrucci Jr RE, Levy SB. Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proc Natl Acad Sci U S A 1980 Jul; 77(7): 3974–7PubMedCrossRefGoogle Scholar
  7. 7.
    Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976 Nov 11; 455(1): 152–62PubMedCrossRefGoogle Scholar
  8. 8.
    Institute of Genome Research (TIGR) microbial database [online]. Available from URL: [Accessed 2003 Nov 11]
  9. 9.
    Lomovskaya O, Warren MS, Lee V. Efflux mechanisms: molecular and clinical aspects. In: Hughes D, Andersson DI, editors. Antibiotic development and resistance. London: Taylor and Francis 2001: 65–90Google Scholar
  10. 10.
    Poole K. Outer membranes and efflux: the path to multidrug resistance in Gram-negative bacteria. Curr Pharm Biotechnol 2002 Jun; 3(2): 77–98PubMedCrossRefGoogle Scholar
  11. 11.
    Paulsen IT, Lewis K. Microbial multidrug efflux. Wynmondham: Horizon Press, 2002Google Scholar
  12. 12.
    Fath MJ, Kolter R. ABC transporters: bacterial exporters. Microbiol Rev 1993 Dec; 57(4): 995–1017PubMedGoogle Scholar
  13. 13.
    Higgins CF. ABC transporters: physiology, structure and mechanism: an overview. Res Microbiol 2001 Apr–May; 152(3–4): 205–10PubMedCrossRefGoogle Scholar
  14. 14.
    Pao SS, Paulsen IT, Saier Jr MH. Major facilitator superfamily. Microbiol Mol Biol Rev 1998 Mar; 62(1): 1–34PubMedGoogle Scholar
  15. 15.
    Brown MH, Paulsen IT, Skurray RA. The multidrug efflux protein NorM is a prototype of a new family of transporters. Mol Microbiol 1999 Jan; 31(1): 394–5PubMedCrossRefGoogle Scholar
  16. 16.
    Paulsen IT, Skurray RA, Tam R, et al. The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic drugs. Mol Microbiol 1996 Mar; 19(6): 1167–75PubMedCrossRefGoogle Scholar
  17. 17.
    Saier Jr MH, Tam R, Reizer A, et al. Two novel families of bacterial membrane proteins concerned with nodulation, cell division and transport. Mol Microbiol 1994 Mar; 11(5): 841–7PubMedCrossRefGoogle Scholar
  18. 18.
    Nikaido H. Multidrug efflux pumps of gram-negative bacteria. J Bacteriol 1996 Oct; 178(20): 5853–9PubMedGoogle Scholar
  19. 19.
    Paulsen IT, Park JH, Choi PS, et al. A family of gram-negative bacterial outer membrane factors that function in the export of proteins, carbohydrates, drugs and heavy metals from gram-negative bacteria. FEMS Microbiol Lett 1997 Nov 1; 156(1): 1–8PubMedCrossRefGoogle Scholar
  20. 20.
    Johnson JM, Church GM. Alignment and structure prediction of divergent protein families: periplasmic and outer membrane proteins of bacterial efflux pumps. J Mol Biol 1999 Apr 2; 287(3): 695–715PubMedCrossRefGoogle Scholar
  21. 21.
    Dinh T, Paulsen IT, Saier Jr MH. A family of extracytoplasmic proteins that allow transport of large molecules across the outer membranes of gram-negative bacteria. J Bacteriol 1994 Jul; 176(13): 3825–31PubMedGoogle Scholar
  22. 22.
    Saier Jr MH, Paulsen IT, Sliwinski MK, et al. Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria. FASEB J 1998 Mar; 12(3): 265–74PubMedGoogle Scholar
  23. 23.
    Higgins CF. ABC transporters: from microorganisms to man. Annu Rev Cell Biol 1992; 8: 67–113PubMedCrossRefGoogle Scholar
  24. 24.
    Bolhuis H, van Veen HW, Brands JR, et al. Energetics and mechanism of drug transport mediated by the lactococcal multidrug transporter LmrP. J Biol Chem 1996 Sep 27; 271(39): 24123–8PubMedCrossRefGoogle Scholar
  25. 25.
    Kobayashi N, Nishino K, Yamaguchi A. Novel macrolide-specific ABC-type efflux transporter in Escherichia coli. J Bacteriol 2001 Oct; 183(19): 5639–44PubMedCrossRefGoogle Scholar
  26. 26.
    Marger MD, Saier Jr MH. A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport. Trends Biochem Sci 1993 Jan; 18(1): 13–20PubMedCrossRefGoogle Scholar
  27. 27.
    Saier Jr MH, Beatty JT, Goffeau A, et al. The major facilitator superfamily. J Mol Microbiol Biotechnol 1999 Nov; 1(2): 257–79PubMedGoogle Scholar
  28. 28.
    Yoshida H, Bogaki M, Nakamura S, et al. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J Bacteriol 1990 Dec; 172(12): 6942–9PubMedGoogle Scholar
  29. 29.
    Lomovskaya O, Lewis K. Emr, an Escherichia coli locus for multidrug resistance. Proc Natl Acad Sci U S A 1992 Oct 1; 89(19): 8938–42PubMedCrossRefGoogle Scholar
  30. 30.
    Morita Y, Kodama K, Shiota S, et al. NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli. Antimicrob Agents Chemother 1998 Jul; 42(7): 1778–82PubMedGoogle Scholar
  31. 31.
    Chung YJ, Saier Jr MH. SMR-type multidrug resistance pumps. Curr Opin Drug Discov Devel 2001 Mar; 4(2): 237–45PubMedGoogle Scholar
  32. 32.
    Paulsen IT, Brown MH, Skurray RA. Proton-dependent multidrug efflux systems. Microbiol Rev 1996 Dec; 60(4): 575–608PubMedGoogle Scholar
  33. 33.
    Grinius L, Dreguniene G, Goldberg EB, et al. A staphylococcal multidrug resistance gene product is a member of a new protein family. Plasmid 1992 Mar; 27(2): 119–29PubMedCrossRefGoogle Scholar
  34. 34.
    Schuldiner S, Lebendiker M, Yerushalmi H. EmrE, the smallest ion-coupled transporter, provides a unique paradigm for structure-function studies. J Exp Biol 1997 Jan; 200 (Pt 2): 335–41PubMedGoogle Scholar
  35. 35.
    Tseng TT, Gratwick KS, Kollman J, et al. The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J Mol Microbiol Biotechnol 1999 Aug; 1(1): 107–25PubMedGoogle Scholar
  36. 36.
    Grosse C, Grass G, Anton A, et al. Transcriptional organization of the czc heavy-metal homeostasis determinant from Alcaligenes eutrophus. J Bacteriol 1999 Apr; 181(8): 2385–93PubMedGoogle Scholar
  37. 37.
    Droge M, Puhler A, Selbitschka W. Phenotypic and molecular characterization of conjugative antibiotic resistance plasmids isolated from bacterial communities of activated sludge. Mol Gen Genet 2000 Apr; 263(3): 471–82PubMedCrossRefGoogle Scholar
  38. 38.
    Nikaido H. Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis 1998 Aug; 27 Suppl. 1: S32–41PubMedCrossRefGoogle Scholar
  39. 39.
    Ma D, Cook DN, Alberti M, et al. Molecular cloning and characterization of acrA and acrE genes of Escherichia coli. J Bacteriol 1993 Oct; 175(19): 6299–313PubMedGoogle Scholar
  40. 40.
    Fralick JA. Evidence that tolC is required for functioning of the mar/acrAB efflux pump of Escherichia coli. J Bacteriol 1996 Oct; 178(19): 5803–5PubMedGoogle Scholar
  41. 41.
    Poole K, Krebes K, McNally C, et al. Multiple antibiotic resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux operon. J Bacteriol 1993 Nov; 175(22): 7363–72PubMedGoogle Scholar
  42. 42.
    Li XZ, Nikaido H, Poole K. Role of MexA-MexB-OprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1995 Sep; 39(9): 1948–53PubMedCrossRefGoogle Scholar
  43. 43.
    Nikaido H. Outer membrane barrier as a mechanism of antimicrobial resistance. Antimicrob Agents Chemother 1989 Nov; 33(11): 1831–6PubMedCrossRefGoogle Scholar
  44. 44.
    Li XZ, Livermore DM, Nikaido H. Role of efflux pump (s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob Agents Chemother 1994 Aug; 38(8): 1732–41PubMedCrossRefGoogle Scholar
  45. 45.
    Li XZ, Ma D, Livermore DM, et al. Role of efflux pump (s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to β-lactam resistance. Antimicrob Agents Chemother 1994 Aug; 38(8): 1742–52PubMedCrossRefGoogle Scholar
  46. 46.
    Nikaido H. The role of outer membrane and efflux pumps in the resistance of gram-negative bacteria: can we improve drug access? Drug Resist Updat 1998; 1: 93–8PubMedCrossRefGoogle Scholar
  47. 47.
    Nishino K, Yamaguchi A. Analysis of a complete library of putative drug transporter genes in Escherichia coli. J Bacteriol 2001 Oct; 183(20): 5803–12PubMedCrossRefGoogle Scholar
  48. 48.
    Nakamura H. Gene-controlled resistance to acriflavine and other basic dyes in Escherichia coli. J Bacteriol 1965 Jul; 90(1): 8–14PubMedGoogle Scholar
  49. 49.
    Zgurskaya HI, Nikaido H. Bypassing the periplasm: reconstitution of the AcrAB multidrug efflux pump of Escherichia coli. Proc Natl Acad Sci U S A 1999 Jun 22; 96(13): 7190–5PubMedCrossRefGoogle Scholar
  50. 50.
    Magnet S, Courvalin P, Lambert T. Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM 4454. Antimicrob Agents Chemother 2001 Dec; 45(12): 3375–80PubMedCrossRefGoogle Scholar
  51. 51.
    Palumbo JD, Kado CI, Phillips DA. An isoflavonoid-inducible efflux pump in Agrobacterium tumefaciens is involved in competitive colonization of roots. J Bacteriol 1998 Jun; 180(12): 3107–13PubMedGoogle Scholar
  52. 52.
    Peng WT, Nester EW. Characterization of a putative RND-type efflux system in Agrobacterium tumefaciens. Gene 2001 May 30; 270(1–2): 245–52PubMedCrossRefGoogle Scholar
  53. 53.
    Krummenacher P, Narberhaus F. Two genes encoding a putative multidrug efflux pump of the RND/MFP family are cotranscribed with an rpoH gene in Bradyrhizobium japonicum. Gene 2000 Jan 11; 241(2): 247–54PubMedCrossRefGoogle Scholar
  54. 54.
    Burns JL, Wadsworth CD, Barry JJ, et al. Nucleotide sequence analysis of a gene from Burkholderia (Pseudomonas) cepacia encoding an outer membrane lipoprotein involved in multiple antibiotic resistance. Antimicrob Agents Chemother 1996 Feb; 40(2): 307–13PubMedGoogle Scholar
  55. 55.
    Moore RA, DeShazer D, Reckseidler S, et al. Efflux-mediated aminoglycoside and macrolide resistance in Burkholderia pseudomallei. Antimicrob Agents Chemother 1999 Mar; 43(3): 465–70PubMedGoogle Scholar
  56. 56.
    Lin J, Michel LO, Zhang Q. CmeABC functions as a multidrug efflux system in Campylobacter jejuni. Antimicrob Agents Chemother 2002 Jul; 46(7): 2124–31PubMedCrossRefGoogle Scholar
  57. 57.
    Pradel E, Pages JM. The AcrAB-TolC efflux pump contributes to multidrug resistance in the nosocomial pathogen Enterobacter aerogenes. Antimicrob Agents Chemother 2002 Aug; 46(8): 2640–3PubMedCrossRefGoogle Scholar
  58. 58.
    Rosenberg EY, Ma D, Nikaido H. AcrD of Escherichia coli is an aminoglycoside efflux pump. J Bacteriol 2000 Mar; 182(6): 1754–6PubMedCrossRefGoogle Scholar
  59. 59.
    Elkins CA, Nikaido H. Substrate specificity of the RND-type multidrug efflux pumps AcrB and AcrD of Escherichia coli is determined predominantly by two large periplasmic loops. J Bacteriol 2002 Dec; 184(23): 6490–8PubMedCrossRefGoogle Scholar
  60. 60.
    Ma D, Cook DN, Hearst JE, et al. Efflux pumps and drug resistance in gram-negative bacteria. Trends Microbiol 1994 Dec; 2(12): 489–93PubMedCrossRefGoogle Scholar
  61. 61.
    Baranova N, Nikaido H. The baeSR two-component regulatory system activates transcription of the yegMNOB (mdtABCD) transporter gene cluster in Escherichia coli and increases its resistance to novobiocin and deoxycholate. J Bacteriol 2002 Aug; 184(15): 4168–76PubMedCrossRefGoogle Scholar
  62. 62.
    Nagakubo S, Nishino K, Hirata T, et al. The putative response regulator BaeR stimulates multidrug resistance of Escherichia coli via a novel multidrug exporter system, MdtABC. J Bacteriol 2002 Aug; 184(15): 4161–7PubMedCrossRefGoogle Scholar
  63. 63.
    Nishino K, Yamaguchi A. EvgA of the two-component signal transduction system modulates production of the yhiUV multidrug transporter in Escherichia coli. J Bacteriol 2002 Apr; 184(8): 2319–23PubMedCrossRefGoogle Scholar
  64. 64.
    Sanchez L, Pan W, Vinas M, et al. The acrAB homolog of Haemophilus influenzae codes for a functional multidrug efflux pump. J Bacteriol 1997 Nov; 179(21): 6855–7PubMedGoogle Scholar
  65. 65.
    Hagman KE, Pan W, Spratt BG, et al. Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents is modulated by the mtrRCDE efflux system. Microbiology 1995 Mar; 141 (Pt 3): 611–22PubMedCrossRefGoogle Scholar
  66. 66.
    Lucas CE, Balthazar JT, Hagman KE, et al. The MtrR repressor binds the DNA sequence between the mtrR and mtrC genes of Neisseria gonorrhoeae. J Bacteriol 1997 Jul; 179(13): 4123–8PubMedGoogle Scholar
  67. 67.
    Lee EH, Shafer WM. The farAB-encoded efflux pump mediates resistance of gonococci to long-chained antibacterial fatty acids. Mol Microbiol 1999 Aug; 33(4): 839–45PubMedCrossRefGoogle Scholar
  68. 68.
    Ikeda T, Yoshimura F. A resistance-nodulation-cell division family xenobiotic efflux pump in an obligate anaerobe, Porphyromonas gingivalis. Antimicrob Agents Chemother 2002 Oct; 46(10): 3257–60PubMedCrossRefGoogle Scholar
  69. 69.
    Poole K, Tetro K, Zhao Q, et al. Expression of the multidrug resistance operon MexA-MexB-OprM in Pseudomonas aeruginosa: MexR encodes a regulator of operon expression. Antimicrob Agents Chemother 1996 Sep; 40(9): 2021–8PubMedGoogle Scholar
  70. 70.
    Poole K, Gotoh N, Tsujimoto H, et al. Overexpression of the MexC-MexD-OprJ efflux operon in nfxB-type multidrug-resistant strains of Pseudomonas aeruginosa. Mol Microbiol 1996 Aug; 21(4): 713–24PubMedCrossRefGoogle Scholar
  71. 71.
    Kohler T, Michea-Hamzehpour M, Henze U, et al. Characterization of MexE-MexF-OprN, a positively regulated multidrug efflux system of Pseudomonas aeruginosa. Mol Microbiol 1997 Jan; 23(2): 345–54PubMedCrossRefGoogle Scholar
  72. 72.
    Aires JR, Kohler T, Nikaido H, et al. Involvement of an active efflux system in the natural resistance of Pseudomonas aeruginosa to aminoglycosides. Antimicrob Agents Chemother 1999 Nov; 43(11): 2624–8PubMedGoogle Scholar
  73. 73.
    Mine T, Morita Y, Kataoka A, et al. Expression in Escherichia coli of a new multidrug efflux pump, MexXY, from Pseudomonas aeruginosa. Antimicrob Agents Chemother 1999 Feb; 43(2): 415–7PubMedGoogle Scholar
  74. 74.
    Westbrock-Wadman S, Sherman DR, Hickey MJ, et al. Characterization of a Pseudomonas aeruginosa efflux pump contributing to aminoglycoside impermeability. Antimicrob Agents Chemother 1999 Dec; 43(12): 2975–83PubMedGoogle Scholar
  75. 75.
    Aendekerk S, Ghysels B, Cornelis P, et al. Characterization of a new efflux pump, MexGHI-OpmD, from Pseudomonas aeruginosa that confers resistance to vanadium. Microbiology 2002 Aug; 148 (Pt 8): 2371–81PubMedGoogle Scholar
  76. 76.
    Chuanchuen R, Narasaki CT, Schweizer HP. The MexJK efflux pump of Pseudomonas aeruginosa requires OprM for antibiotic efflux but not for efflux of triclosan. J Bacteriol 2002 Sep; 184(18): 5036–44PubMedCrossRefGoogle Scholar
  77. 77.
    Kieboom J, Dennis JJ, de Bont JA, et al. Identification and molecular characterization of an efflux pump involved in Pseudomonas putida S12 solvent tolerance. J Biol Chem 1998 Jan 2; 273(1): 85–91PubMedCrossRefGoogle Scholar
  78. 78.
    Ramos JL, Duque E, Godoy P, et al. Efflux pumps involved in toluene tolerance in Pseudomonas putida DOT-T1E. J Bacteriol 1998 Jul; 180(13): 3323–9PubMedGoogle Scholar
  79. 79.
    Fukumori F, Hirayama H, Takami H, et al. Isolation and transposon mutagenesis of a Pseudomonas putida KT2442 toluene-resistant variant: involvement of an efflux system in solvent resistance. Extremophiles 1998 Nov; 2(4): 395–400PubMedCrossRefGoogle Scholar
  80. 80.
    Mosqueda G, Ramos JL. A set of genes encoding a second toluene efflux system in Pseudomonas putida DOT-T1E is linked to the tod genes for toluene metabolism. J Bacteriol 2000 Feb; 182(4): 937–43PubMedCrossRefGoogle Scholar
  81. 81.
    Rojas A, Duque E, Mosqueda G, et al. Three efflux pumps are required to provide efficient tolerance to toluene in Pseudomonas putida DOT-T1E. J Bacteriol 2001 Jul; 183(13): 3967–73PubMedCrossRefGoogle Scholar
  82. 82.
    Li XZ, Zhang L, Poole K. SmeC, an outer membrane multidrug efflux protein of Stenotrophomonas maltophilia. Antimicrob Agents Chemother 2002 Feb; 46(2): 333–43PubMedCrossRefGoogle Scholar
  83. 83.
    Zhang L, Li XZ, Poole K. SmeDEF multidrug efflux pump contributes to intrinsic multidrug resistance in Stenotrophomonas maltophilia. Antimicrob Agents Chemother 2001 Dec; 45(12): 3497–503PubMedCrossRefGoogle Scholar
  84. 84.
    Alonso A, Martinez JL. Cloning and characterization of SmeDEF, a novel multidrug efflux pump from Stenotrophomonas maltophilia. Antimicrob Agents Chemother 2000 Nov; 44(11): 3079–86PubMedCrossRefGoogle Scholar
  85. 85.
    Kumar A, Worobec EA. Fluoroquinolone resistance of Serratia marcescens: involvement of a proton gradient-dependent efflux pump. J Antimicrob Chemother 2002 Oct; 50(4): 593–6PubMedCrossRefGoogle Scholar
  86. 86.
    Nikaido H, Basina M, Nguyen V, et al. Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those β-lactam antibiotics containing lipophilic side chains. J Bacteriol 1998 Sep; 180(17): 4686–92PubMedGoogle Scholar
  87. 87.
    Lacroix FJ, Cloeckaert A, Grepinet O, et al. Salmonella typhimurium acrB-like gene: identification and role in resistance to biliary salts and detergents and in murine infection. FEMS Microbiol Lett 1996 Jan 15; 135(2–3): 161–7PubMedCrossRefGoogle Scholar
  88. 88.
    Sulavik MC, Houseweart C, Cramer C, et al. Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes. Antimicrob Agents Chemother 2001 Apr; 45(4): 1126–36PubMedCrossRefGoogle Scholar
  89. 89.
    Furukawa H, Tsay JT, Jackowski S, et al. resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB. J Bacteriol 1993 Jun; 175(12): 3723–9PubMedGoogle Scholar
  90. 90.
    Bohn C, Bouloc P. The Escherichia coli cmlA gene encodes the multidrug efflux pump Cmr/MdfA and is responsible for isopropyl-β-D-thiogalactopyranoside exclusion and spectinomycin sensitivity. J Bacteriol 1998 Nov; 180(22): 6072–5PubMedGoogle Scholar
  91. 91.
    Nilsen IW, Bakke I, Vader A, et al. Isolation of cmr, a novel Escherichia coli chloramphenicol resistance gene encoding a putative efflux pump. J Bacteriol 1996 Jun; 178(11): 3188–93PubMedGoogle Scholar
  92. 92.
    Edgar R, Bibi E. A single membrane-embedded negative charge is critical for recognizing positively charged drugs by the Escherichia coli multidrug resistance protein MdfA. EMBO J 1999 Feb 15; 18(4): 822–32PubMedCrossRefGoogle Scholar
  93. 93.
    Mine T, Morita Y, Kataoka A, et al. Evidence for chloramphenicol/H+ antiport in Cmr (MdfA) system of Escherichia coli and properties of the antiporter. J Biochem (Tokyo) 1998 Jul; 124(1): 187–93CrossRefGoogle Scholar
  94. 94.
    Dorman CJ, Foster TJ, Shaw WV. Nucleotide sequence of the R26 chloramphenicol resistance determinant and identification of its gene product. Gene 1986; 41(2–3): 349–53PubMedCrossRefGoogle Scholar
  95. 95.
    Ploy MC, Courvalin P, Lambert T. Characterization of In40 of Enterobacter aerogenes BM2688, a class 1 integron with two new gene cassettes, cmlA2 and qacF. Antimicrob Agents Chemother 1998 Oct; 42(10): 2557–63PubMedGoogle Scholar
  96. 96.
    Toro CS, Lobos SR, Calderon I, et al. Clinical isolate of a porinless Salmonella typhi resistant to high levels of chloram-phenicol. Antimicrob Agents Chemother 1990 Sep; 34(9): 1715–9PubMedCrossRefGoogle Scholar
  97. 97.
    Bissonnette L, Champetier S, Buisson JP, et al. Characterization of the nonenzymatic chloramphenicol resistance (cmlA) gene of the In4 integron of Tn1696: similarity of the product to transmembrane transport proteins. J Bacteriol 1991 Jul; 173(14): 4493–502PubMedGoogle Scholar
  98. 98.
    Kim E, Aoki T. Sequence analysis of the florfenicol resistance gene encoded in the transferable R-plasmid of a fish pathogen, Pasteurella piscicida. Microbiol Immunol 1996; 40(9): 665–9PubMedGoogle Scholar
  99. 99.
    Bolton LF, Kelley LC, Lee MD, et al. Detection of multidrug-resistant Salmonella enterica serotype typhimurium DT104 based on a gene which confers cross-resistance to florfenicol and chloramphenicol. J Clin Microbiol 1999 May; 37(5): 1348–51PubMedGoogle Scholar
  100. 100.
    Boyd D, Peters GA, Cloeckaert A, et al. Complete nucleotide sequence of a 43-kilobase genomic island associated with the multidrug resistance region of Salmonella enterica serovar Typhimurium DT104 and its identification in phage type DT120 and serovar Agona. J Bacteriol 2001 Oct; 183(19): 5725–32PubMedCrossRefGoogle Scholar
  101. 101.
    White DG, Hudson C, Maurer JJ, et al. Characterization of chloramphenicol and florfenicol resistance in Escherichia coli associated with bovine diarrhea. J Clin Microbiol 2000 Dec; 38(12): 4593–8PubMedGoogle Scholar
  102. 102.
    Schuldiner S, Granot D, Steiner S, et al. Precious things come in little packages. J Mol Microbiol Biotechnol 2001 Apr; 3(2): 155–62PubMedGoogle Scholar
  103. 103.
    Yerushalmi H, Schuldiner S. A model for coupling of H+ and substrate fluxes based on ‘time-sharing’ of a common binding site. Biochemistry 2000 Dec 5; 39(48): 14711–9PubMedCrossRefGoogle Scholar
  104. 104.
    Yerushalmi H, Schuldiner S. A common binding site for substrates and protons in EmrE, an ion-coupled multidrug transporter. FEBS Lett 2000 Jun 30; 476(1–2): 93–7PubMedCrossRefGoogle Scholar
  105. 105.
    Yerushalmi H, Schuldiner S. An essential glutamyl residue in EmrE, a multidrug antiporter from Escherichia coli. J Biol Chem 2000 Feb 25; 275(8): 5264–9PubMedCrossRefGoogle Scholar
  106. 106.
    Chung YJ, Saier Jr MH. Overexpression of the Escherichia colisugE gene confers resistance to a narrow range of quaternary ammonium compounds. J Bacteriol 2002 May; 184(9): 2543–5PubMedCrossRefGoogle Scholar
  107. 107.
    Levy SB. Active efflux mechanisms for antimicrobial resistance. Antimicrob Agents Chemother 1992 Apr; 36(4): 695–703PubMedCrossRefGoogle Scholar
  108. 108.
    Thanassi DG, Suh GS, Nikaido H. Role of outer membrane barrier in efflux-mediated tetracycline resistance of Escherichia coli. J Bacteriol 1995 Feb; 177(4): 998–1007PubMedGoogle Scholar
  109. 109.
    Yamaguchi A, Udagawa T, Sawai T. Transport of divalent cations with tetracycline as mediated by the transposon Tn10-encoded tetracycline resistance protein. J Biol Chem 1990 Mar 25; 265(9): 4809–13PubMedGoogle Scholar
  110. 110.
    Linton KJ, Higgins CF. The Escherichia coli ATP-binding cassette (ABC) proteins. Mol Microbiol 1998 Apr; 28(1): 5–13PubMedCrossRefGoogle Scholar
  111. 111.
    Allikmets R, Gerrard B, Court D, et al. Cloning and organization of the abc and mdl genes of Escherichia coli: relationship to eukaryotic multidrug resistance. Gene 1993 Dec 22; 136(1–2): 231–6PubMedCrossRefGoogle Scholar
  112. 112.
    Nikaido H. Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 1994 Apr 15; 264(5157): 382–8PubMedCrossRefGoogle Scholar
  113. 113.
    Poole K, Heinrichs DE, Neshat S. Cloning and sequence analysis of an EnvCD homologue in Pseudomonas aeruginosa: regulation by iron and possible involvement in the secretion of the siderophore pyoverdine. Mol Microbiol 1993 Nov; 10(3): 529–44PubMedCrossRefGoogle Scholar
  114. 114.
    Nikaido H. Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol 2001 Jun; 12(3): 215–23PubMedCrossRefGoogle Scholar
  115. 115.
    Poole K. Multidrug efflux pumps and antimicrobial resistance in Pseudomonas aeruginosa and related organisms. J Mol Microbiol Biotechnol 2001 Apr; 3(2): 255–64PubMedGoogle Scholar
  116. 116.
    Stover CK, Pham XQ, Erwin AL, et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 2000 Aug 31; 406(6799): 959–64PubMedCrossRefGoogle Scholar
  117. 117.
    Masuda N, Ohya S. Cross-resistance to meropenem, cephems, and quinolones in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1992 Sep; 36(9): 1847–51PubMedCrossRefGoogle Scholar
  118. 118.
    Masuda N, Sakagawa E, Ohya S. Outer membrane proteins responsible for multiple drug resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1995 Mar; 39(3): 645–9PubMedCrossRefGoogle Scholar
  119. 119.
    Srikumar R, Paul CJ, Poole K. Influence of mutations in the MexR repressor gene on expression of the MexA-MexB-OprM multidrug efflux system of Pseudomonas aeruginosa. J Bacteriol 2000 Mar; 182(5): 1410–4PubMedCrossRefGoogle Scholar
  120. 120.
    Ziha-Zarifi I, Llanes C, Köhler T, et al. In vivo emergence of multidrug-resistant mutants of Pseudomonas aeruginosa over-expressing the active efflux system MexA-MexB-OprM. Antimicrob Agents Chemother 1999 Feb; 43(2): 287–91PubMedGoogle Scholar
  121. 121.
    Köhler T, Kok M, Michea-Hamzehpour M, et al. Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1996 Oct; 40(10): 2288–90PubMedGoogle Scholar
  122. 122.
    Li XZ, Zhang L, Srikumar R, et al. β-Lactamase inhibitors are substrates for the multidrug efflux pumps of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1998 Feb; 42(2): 399–403PubMedGoogle Scholar
  123. 123.
    Schweizer HP. Intrinsic resistance to inhibitors of fatty acid biosynthesis in Pseudomonas aeruginosa is due to efflux: application of a novel technique for generation of unmarked chromosomal mutations for the study of efflux systems. Antimicrob Agents Chemother 1998 Feb; 42(2): 394–8PubMedGoogle Scholar
  124. 124.
    Srikumar R, Li XZ, Poole K. Inner membrane efflux components are responsible for β-lactam specificity of multidrug efflux pumps in Pseudomonas aeruginosa. J Bacteriol 1997 Dec; 179(24): 7875–81PubMedGoogle Scholar
  125. 125.
    Li XZ, Zhang L, Poole K. Role of the multidrug efflux systems of Pseudomonas aeruginosa in organic solvent tolerance. J Bacteriol 1998 Jun; 180(11): 2987–91PubMedGoogle Scholar
  126. 126.
    Srikumar R, Kon T, Gotoh N, et al. Expression of Pseudomonas aeruginosa multidrug efflux pumps MexA-MexB-OprM and MexC-MexD-OprJ in a multidrug-sensitive Escherichia coli strain. Antimicrob Agents Chemother 1998 Jan; 42(1): 65–71PubMedGoogle Scholar
  127. 127.
    Li XZ, Poole K. Organic solvent-tolerant mutants of Pseudomonas aeruginosa display multiple antibiotic resistance. Can J Microbiol 1999 Jan; 45(1): 18–22PubMedGoogle Scholar
  128. 128.
    Masuda N, Sakagawa E, Ohya S, et al. Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-OprM efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2000 Dec; 44(12): 3322–7PubMedCrossRefGoogle Scholar
  129. 129.
    Trias J, Nikaido H. Outer membrane protein D2 catalyzes facilitated diffusion of carbapenems and penems through the outer membrane of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1990 Jan; 34(1): 52–7PubMedCrossRefGoogle Scholar
  130. 130.
    Okamoto K, Gotoh N, Nishino T. Pseudomonas aeruginosa reveals high intrinsic resistance to penem antibiotics: penem resistance mechanisms and their interplay. Antimicrob Agents Chemother 2001 Jul; 45(7): 1964–71PubMedCrossRefGoogle Scholar
  131. 131.
    Okamoto K, Gotoh N, Nishino T. Extrusion of penem antibiotics by multicomponent efflux systems MexAB-OprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2002 Aug; 46(8): 2696–9PubMedCrossRefGoogle Scholar
  132. 132.
    Zhao Q, Li XZ, Srikumar R, et al. Contribution of outer membrane efflux protein OprM to antibiotic resistance in Pseudomonas aeruginosa independent of MexAB. Antimicrob Agents Chemother 1998 Jul; 42(7): 1682–8PubMedGoogle Scholar
  133. 133.
    Gotoh N, Tsujimoto H, Nomura A, et al. Functional replacement of OprJ by OprM in the MexCD-OprJ multidrug efflux system of Pseudomonas aeruginosa. FEMS Microbiol Lett 1998 Aug 1; 165(1): 21–7PubMedGoogle Scholar
  134. 134.
    Maseda H, Yoneyama H, Nakae T. Assignment of the substrate-selective subunits of the MexEF-OprN multidrug efflux pump of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2000 Mar; 44(3): 658–64PubMedCrossRefGoogle Scholar
  135. 135.
    Passador L, Cook JM, Gambello MJ, et al. Expression of Pseudomonas aeruginosa virulence genes requires cell-to-cell communication. Science 1993 May 21; 260(5111): 1127–30PubMedCrossRefGoogle Scholar
  136. 136.
    Hastings JW, Greenberg EP. Quorum sensing: the explanation of a curious phenomenon reveals a common characteristic of bacteria. J Bacteriol 1999 May; 181(9): 2667–8PubMedGoogle Scholar
  137. 137.
    Pearson JP, Van Delden C, Iglewski BH. Active efflux and diffusion are involved in transport of Pseudomonas aeruginosa cell-to-cell signals. J Bacteriol 1999 Feb; 181(4): 1203–10PubMedGoogle Scholar
  138. 138.
    Evans K, Passador L, Srikumar R, et al. Influence of the MexAB-OprM multidrug efflux system on quorum sensing in Pseudomonas aeruginosa. J Bacteriol 1998 Oct; 180(20): 5443–7PubMedGoogle Scholar
  139. 139.
    Hirakata Y, Srikumar R, Poole K, et al. Multidrug efflux systems play an important role in the invasiveness of Pseudomonas aeruginosa. J Exp Med 2002 Jul 1; 196(1): 109–18PubMedCrossRefGoogle Scholar
  140. 140.
    Chuanchuen R, Beinlich K, Hoang TT, et al. Cross-resistance between triclosan and antibiotics in Pseudomonas aeruginosa is mediated by multidrug efflux pumps: exposure of a susceptible mutant strain to triclosan selects nfxB mutants overexpressing MexCD-OprJ. Antimicrob Agents Chemother 2001 Feb; 45(2): 428–32PubMedCrossRefGoogle Scholar
  141. 141.
    Morita Y, Komori Y, Mima T, et al. Construction of a series of mutants lacking all of the four major mex operons for multidrug efflux pumps or possessing each one of the operons from Pseudomonas aeruginosa PAO1: MexCD-OprJ is an inducible pump. FEMS Microbiol Lett 2001 Aug 7; 202(1): 139–43PubMedCrossRefGoogle Scholar
  142. 142.
    Masuda N, Gotoh N, Ohya S, et al. Quantitative correlation between susceptibility and OprJ production in NfxB mutants of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1996 Apr; 40(4): 909–13PubMedGoogle Scholar
  143. 143.
    Li XZ, Barre N, Poole K. Influence of the MexA-MexB-OprM multidrug efflux system on expression of the MexC-MexD-OprJ and MexE-MexF-OprN multidrug efflux systems in Pseudomonas aeruginosa. J Antimicrob Chemother 2000 Dec; 46(6): 885–93PubMedCrossRefGoogle Scholar
  144. 144.
    Gotoh N, Tsujimoto H, Tsuda M, et al. Characterization of the MexC-MexD-OprJ multidrug efflux system in △MexA-MexB-OprM mutants of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1998 Aug; 42(8): 1938–43PubMedGoogle Scholar
  145. 145.
    Masuda N, Sakagawa E, Ohya S, et al. Hypersusceptibility of the Pseudomonas aeruginosa nfxB mutant to β-lactams due to reduced expression of the AmpC β-lactamase. Antimicrob Agents Chemother 2001 Apr; 45(4): 1284–6PubMedCrossRefGoogle Scholar
  146. 146.
    Ochs MM, McCusker MP, Bains M, et al. Negative regulation of the Pseudomonas aeruginosa outer membrane porin OprD selective for imipenem and basic amino acids. Antimicrob Agents Chemother 1999 May; 43(5): 1085–90PubMedGoogle Scholar
  147. 147.
    Köhler T, van Delden C, Curty LK, et al. Overexpression of the MexEF-OprN multidrug efflux system affects cell-to-cell signaling in Pseudomonas aeruginosa. J Bacteriol 2001 Sep; 183(18): 5213–22PubMedCrossRefGoogle Scholar
  148. 148.
    Alonso A, Martinez JL. Multiple antibiotic resistance in Stenotrophomonas maltophilia. Antimicrob Agents Chemother 1997 May; 41(5): 1140–2PubMedGoogle Scholar
  149. 149.
    Zhang L, Li XZ, Poole K. Multiple antibiotic resistance in Stenotrophomonas maltophilia: involvement of a multidrug efflux system. Antimicrob Agents Chemother 2000 Feb; 44(2): 287–93PubMedCrossRefGoogle Scholar
  150. 150.
    Alonso A, Martinez JL. Expression of multidrug efflux pump SmeDEF by clinical isolates of Stenotrophomonas maltophilia. Antimicrob Agents Chemother 2001 Jun; 45(6): 1879–81PubMedCrossRefGoogle Scholar
  151. 151.
    Burns JL, Hedin LA, Lien DM. Chloramphenicol resistance in Pseudomonas cepacia because of decreased permeability. Antimicrob Agents Chemother 1989 Feb; 33(2): 136–41PubMedCrossRefGoogle Scholar
  152. 152.
    Zhang L, Li XZ, Poole K. Fluoroquinolone susceptibilities of efflux-mediated multidrug-resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Burkholderia cepacia. J Antimicrob Chemother 2001 Oct; 48(4): 549–52PubMedCrossRefGoogle Scholar
  153. 153.
    Kim K, Lee S, Lee K, et al. Isolation and characterization of toluene-sensitive mutants from the toluene-resistant bacterium Pseudomonas putida GM 73. J Bacteriol 1998 Jul; 180(14): 3692–6PubMedGoogle Scholar
  154. 154.
    Sparling PF, Sarubbi Jr FA, Blackman E. Inheritance of low-level resistance to penicillin, tetracycline, and chloramphenicol in Neisseria gonorrhoeae. J Bacteriol 1975 Nov; 124(2): 740–9PubMedGoogle Scholar
  155. 155.
    Guymon LF, Sparling PF. Altered crystal violet permeability and lytic behavior in antibiotic-resistant and -sensitive mutants of Neisseria gonorrhoeae. J Bacteriol 1975 Nov; 124(2): 757–63PubMedGoogle Scholar
  156. 156.
    Lysko PG, Morse SA. Neisseria gonorrhoeae cell envelope: permeability to hydrophobic molecules. J Bacteriol 1981 Feb; 145(2): 946–52PubMedGoogle Scholar
  157. 157.
    Pan W, Spratt BG. Regulation of the permeability of the gonococcal cell envelope by the mtr system. Mol Microbiol 1994 Feb; 11(4): 769–75PubMedCrossRefGoogle Scholar
  158. 158.
    Rouquette C, Harmon JB, Shafer WM. Induction of the mtrCDE-encoded efflux pump system of Neisseria gonorrhoeae requires MtrA, an AraC-like protein. Mol Microbiol 1999 Aug; 33(3): 651–8PubMedCrossRefGoogle Scholar
  159. 159.
    Delahay RM, Robertson BD, Balthazar JT, et al. Involvement of the gonococcal MtrE protein in the resistance of Neisseria gonorrhoeae to toxic hydrophobic agents. Microbiology 1997 Jul; 143 (Pt 7): 2127–33PubMedCrossRefGoogle Scholar
  160. 160.
    Hagman KE, Lucas CE, Balthazar JT, et al. The MtrD protein of Neisseria gonorrhoeae is a member of the resistance/nodulation/division protein family constituting part of an efflux system. Microbiology 1997 Jul; 143 (Pt 7): 2117–25PubMedCrossRefGoogle Scholar
  161. 161.
    Zarantonelli L, Borthagaray G, Lee EH, et al. Decreased susceptibility to azithromycin and erythromycin mediated by a novel mtr(R) promoter mutation in Neisseria gonorrhoeae. J Antimicrob Chemother 2001 May; 47(5): 651–4PubMedCrossRefGoogle Scholar
  162. 162.
    McFarland L, Mietzner TA, Knapp JS, et al. Gonococcal sensitivity to fecal lipids can be mediated by an Mtr-independent mechanism. J Clin Microbiol 1983 Jul; 18(1): 121–7PubMedGoogle Scholar
  163. 163.
    Morse SA, Lysko PG, McFarland L, et al. Gonococcal strains from homosexual men have outer membranes with reduced permeability to hydrophobic molecules. Infect Immun 1982 Aug; 37(2): 432–8PubMedGoogle Scholar
  164. 164.
    Shafer WM, Veal WL, Lee EH, et al. Genetic organization and regulation of antimicrobial efflux systems possessed by Neisseria gonorrhoeae and N. imeningitidis. J Mol Microbiol Biotechnol 2001 Apr; 3(2): 219–24PubMedGoogle Scholar
  165. 165.
    Garg P, Chakraborty S, Basu I, et al. Expanding multiple antibiotic resistance among clinical strains of Vibrio cholerae isolated from 1992–7 in Calcutta, India. Epidemiol Infect 2000 Jun; 124(3): 393–9PubMedCrossRefGoogle Scholar
  166. 166.
    Huda MN, Morita Y, Kuroda T, et al. Na+-driven multidrug efflux pump VcmA from Vibrio cholerae non-O1, a nonhalophilic bacterium. FEMS Microbiol Lett 2001 Sep 25; 203(2): 235–9PubMedCrossRefGoogle Scholar
  167. 167.
    Colmer JA, Fralick JA, Hamood AN. Isolation and characterization of a putative multidrug resistance pump from Vibrio cholerae. Mol Microbiol 1998 Jan; 27(1): 63–72PubMedCrossRefGoogle Scholar
  168. 168.
    Baranwal S, Dey K, Ramamurthy T, et al. Role of active efflux in association with target gene mutations in fluoroquinolone resistance in clinical isolates of Vibrio cholerae. Antimicrob Agents Chemother 2002 Aug; 46(8): 2676–8PubMedCrossRefGoogle Scholar
  169. 169.
    Miyamae S, Ueda O, Yoshimura F, et al. A MATE family multidrug efflux transporter pumps out fluoroquinolones in Bacteroides thetaiotaomicron. Antimicrob Agents Chemother 2001 Dec; 45(12): 3341–6PubMedCrossRefGoogle Scholar
  170. 170.
    Wigfield SM, Rigg GP, Kavari M, et al. Identification of an immunodominant drug efflux pump in Burkholderia cepacia. J Antimicrob Chemother 2002 Apr; 49(4): 619–24PubMedCrossRefGoogle Scholar
  171. 171.
    Miyamae CC, Valvano MA. Cloning and characterization of the Burkholderia vietnamiensis norM gene encoding a multi-drug efflux protein. FEMS Microbiol Lett 2002 Oct 8; 215(2): 279–83CrossRefGoogle Scholar
  172. 172.
    Nishino K, Yamaguchi A. Overexpression of the response regulator evgAof the two-component signal transduction system modulates multidrug resistance conferred by multidrug resistance transporters. J Bacteriol 2001 Feb; 183(4): 1455–8PubMedCrossRefGoogle Scholar
  173. 173.
    Naroditskaya V, Schlosser MJ, Fang NY, et al. An E. coli gene emrD is involved in adaptation to low energy shock. Biochem Biophys Res Commun 1993 Oct 29; 196(2): 803–9PubMedCrossRefGoogle Scholar
  174. 174.
    Phadtare S, Yamanaka K, Kato I, et al. Antibacterial activity of 4,5-dihydroxy-2-cyclopentan-1-one (DHCP) and cloning of a gene conferring DHCP resistance in Escherichia coli. J Mol Microbiol Biotechnol 2001 Jul; 3(3): 461–5PubMedGoogle Scholar
  175. 175.
    Yerushalmi H, Lebendiker M, Schuldiner S. EmrE, an Escherichia coli12-kDa multidrug transporter, exchanges toxic cations and H+ and is soluble in organic solvents. J Biol Chem 1995 Mar 24; 270(12): 6856–63PubMedCrossRefGoogle Scholar
  176. 176.
    Turner RJ, Taylor DE, Weiner JH. Expression of Escherichia coliTehA gives resistance to antiseptics and disinfectants similar to that conferred by multidrug resistance efflux pumps. Antimicrob Agents Chemother 1997 Feb; 41(2): 440–4PubMedGoogle Scholar
  177. 177.
    Li X-Z, Poole K, Nikaido H. Contributions of MexAB-OprM and an EmrE homolog to intrinsic resistance of Pseudomonas aeruginosato aminoglycosides and dyes. Antimicrob Agents Chemother 2003; 47(1): 27–33CrossRefGoogle Scholar
  178. 178.
    Hongo E, Morimyo M, Mita K, et al. The methyl viologen-resistance-encoding gene smvAof Salmonellatyphimurium. Gene 1994 Oct 11; 148(1): 173–4PubMedCrossRefGoogle Scholar
  179. 179.
    Santiviago CA, Fuentes JA, Bueno SM, et al. The Salmonella enterica sv. Typhimurium smvA, yddG and ompD (porin) genes are required for the efficient efflux of methyl viologen. Mol Microbiol 2002 Nov; 46(3): 687–98PubMedCrossRefGoogle Scholar
  180. 180.
    Baquero F. Gram-positive resistance: challenge for the development of new antibiotics. J Antimicrob Chemother 1997 May; 39 Suppl. A: 1–6PubMedCrossRefGoogle Scholar
  181. 181.
    Hooper DC. Fluoroquinolone resistance among Gram-positive cocci. Lancet Infect Dis 2002 Sep; 2(9): 530–8PubMedCrossRefGoogle Scholar
  182. 182.
    Ahmed M, Lyass L, Markham PN, et al. Two highly similar multidrug transporters of Bacillussubtiliswhose expression is differentially regulated. J Bacteriol 1995 Jul; 177(14): 3904–10PubMedGoogle Scholar
  183. 183.
    Baranova NN, Danchin A, Neyfakh AA. Mta, a global MerR-type regulator of the Bacillussubtilismultidrug-efflux transporters. Mol Microbiol 1999 Mar; 31(5): 1549–59PubMedCrossRefGoogle Scholar
  184. 184.
    Woolridge DP, Vazquez-Laslop N, Markham PN, et al. Efflux of the natural polyamine spermidine facilitated by the Bacillus subtilismultidrug transporter Blt. J Biol Chem 1997 Apr 4; 272(14): 8864–6PubMedCrossRefGoogle Scholar
  185. 185.
    Masaoka Y, Ueno Y, Morita Y, et al. A two-component multidrug efflux pump, EbrAB, in Bacillussubtilis. J Bacteriol 2000 Apr; 182(8): 2307–10PubMedCrossRefGoogle Scholar
  186. 186.
    Davis DR, McAlpine JB, Pazoles CJ, et al. Enterococcus faecalismulti-drug resistance transporters: application for antibiotic discovery. J Mol Microbiol Biotechnol 2001 Apr; 3(2): 179–84PubMedGoogle Scholar
  187. 187.
    Singh KV, Weinstock GM, Murray BE. An Enterococcusfaecalis ABC homologue (Lsa) is required for the resistance of this species to clindamycin and quinupristin-dalfopristin. Antimicrob Agents Chemother 2002 Jun; 46(6): 1845–50PubMedCrossRefGoogle Scholar
  188. 188.
    Jonas BM, Murray BE, Weinstock GM. Characterization of emeA, a norAhomolog and multidrug resistance efflux pump, in Enterococcusfaecalis. Antimicrob Agents Chemother 2001 Dec; 45(12): 3574–9PubMedCrossRefGoogle Scholar
  189. 189.
    Lynch C, Courvalin P, Nikaido H. Active efflux of antimicrobial agents in wild-type strains of enterococci. Antimicrob Agents Chemother 1997 Apr; 41(4): 869–71PubMedGoogle Scholar
  190. 190.
    Bolhuis H, van Veen HW, Molenaar D, et al. Multidrug resistance in Lactococcuslactis: evidence for ATP-dependent drug extrusion from the inner leaflet of the cytoplasmic membrane. EMBO J 1996 Aug 15; 15(16): 4239–45PubMedGoogle Scholar
  191. 191.
    Bolhuis H, Poelarends G, van Veen HW, et al. The lactococcal imrPgene encodes a proton motive force-dependent drug transporter. J Biol Chem 1995 Nov 3; 270(44): 26092–8PubMedCrossRefGoogle Scholar
  192. 192.
    Perreten V, Schwarz FV, Teuber M, et al. Mdt (A), a new efflux protein conferring multiple antibiotic resistance in Lactococcus lactisand Escherichiacoli. Antimicrob Agents Chemother 2001 Apr; 45(4): 1109–14PubMedCrossRefGoogle Scholar
  193. 193.
    Mata MT, Baquero F, Perez-Diaz JC. A multidrug efflux transporter in Listeriamonocytogenes. FEMS Microbiol Lett 2000 Jun 15; 187(2): 185–8PubMedCrossRefGoogle Scholar
  194. 194.
    Ross JI, Eady EA, Cove JH, et al. Identification of a chromosomally encoded ABC-transport system with which the staphylococcal erythromycin exporter MsrA may interact. Gene 1995 Feb 3; 153(1): 93–8PubMedCrossRefGoogle Scholar
  195. 195.
    Fournier B, Aras R, Hooper DC. Expression of the multidrug resistance transporter NorA from Staphylococcusaureusis modified by a two-component regulatory system. J Bacteriol 2000 Feb; 182(3): 664–71PubMedCrossRefGoogle Scholar
  196. 196.
    Littlejohn TG, Pauken IT, Gillespie MT, et al. Substrate specificity and energetics of antiseptic and disinfectant resistance in Staphylococcusaureus. FEMS Microbiol Lett 1992 Aug 15; 74(2–3): 259–65PubMedCrossRefGoogle Scholar
  197. 197.
    Clancy J, Dib-Hajj F, Petitpas JW, et al. Cloning and characterization of a novel macrolide efflux gene, mreA, from Streptococcus agalactiae. Antimicrob Agents Chemother 1997 Dec; 41(12): 2719–23PubMedGoogle Scholar
  198. 198.
    Gill MJ, Brenwald NP, Wise R. Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in Streptococcuspneumoniae. Antimicrob Agents Chemother 1999 Jan; 43(1): 187–9PubMedGoogle Scholar
  199. 199.
    Tait-Kamradt A, Clancy J, Cronan M, et al. mefEis necessary for the erythromycin-resistant M phenotype in Streptococcus pneumoniae. Antimicrob Agents Chemother 1997 Oct; 41(10): 2251–5PubMedGoogle Scholar
  200. 200.
    Clancy J, Petitpas J, Dib-Hajj F, et al. Molecular cloning and functional analysis of a novel macrolide-resistance determinant, mefA, from Streptococcuspyogenes. Mol Microbiol 1996 Dec; 22(5): 867–79PubMedCrossRefGoogle Scholar
  201. 201.
    Ainsa JA, Blokpoel MC, Otal I, et al. Molecular cloning and characterization of Tap, a putative multidrug efflux pump present in Mycobacteriumfortuitumand Mycobacteriumtuberculosis. J Bacteriol 1998 Nov; 180(22): 5836–43PubMedGoogle Scholar
  202. 202.
    Takiff HE, Cimino M, Musso MC, et al. Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacteriumsmegmatis. Proc Natl Acad Sci U S A 1996 Jan 9; 93(1): 362–6PubMedCrossRefGoogle Scholar
  203. 203.
    Choudhuri BS, Sen S, Chakrabarti P. Isoniazid accumulation in Mycobacteriumsmegmatisis modulated by proton motive force-driven and ATP-dependent extrusion systems. Biochem Biophys Res Commun 1999 Mar 24; 256(3): 682–4PubMedCrossRefGoogle Scholar
  204. 204.
    Choudhuri BS, Bhakta S, Barik R, et al. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrAand drrBof Mycobacterium tuberculosis. Biochem J 2002 Oct 1; 367 (Pt 1): 279–85PubMedCrossRefGoogle Scholar
  205. 205.
    Doran JL, Pang Y, Mdluli KE, et al. Mycobacteriumtuberculosis efpAencodes an efflux protein of the QacA transporter family. Clin Diagn Lab Immunol 1997 Jan; 4(1): 23–32PubMedGoogle Scholar
  206. 206.
    Silva PE, Bigi F, de la Paz Santangelo M, et al. Characterization of P55, a multidrug efflux pump in Mycobacteriumbovisand Mycobacteriumtuberculosis. Antimicrob Agents Chemother 2001 Mar; 45(3): 800–4PubMedCrossRefGoogle Scholar
  207. 207.
    De Rossi E, Branzoni M, Cantoni R, et al. mmr, a Mycobacterium tuberculosisgene conferring resistance to small cationic dyes and inhibitors. J Bacteriol 1998 Nov; 180(22): 6068–71PubMedGoogle Scholar
  208. 208.
    Carbon C. MRSA and MRSE: is there an answer? Clin Microbiol Infect 2000 Aug; 6 Suppl. 2: 17–22CrossRefGoogle Scholar
  209. 209.
    Tennent JM, Lyon BR, Midgley M, et al. Physical and biochemical characterization of the qacAgene encoding antiseptic and disinfectant resistance in Staphylococcusaureus. J Gen Microbiol 1989 Jan; 135 (Pt 1): 1–10PubMedGoogle Scholar
  210. 210.
    Paulsen IT, Brown MH, Littlejohn TG, et al. Multidrug resistance proteins QacA and QacB from Staphylococcusaureus: membrane topology and identification of residues involved in substrate specificity. Proc Natl Acad Sci U S A 1996 Apr 16; 93(8): 3630–5PubMedCrossRefGoogle Scholar
  211. 211.
    Noguchi N, Hase M, Kitta M, et al. Antiseptic susceptibility and distribution of antiseptic-resistance genes in methicillin-resistant Staphylococcusaureus. FEMS Microbiol Lett 1999 Mar 15; 172(2): 247–53PubMedCrossRefGoogle Scholar
  212. 212.
    Kaatz GW, Seo SM, Ruble CA. Efflux-mediated fluoroquinolone resistance in Staphylococcusaureus. Antimicrob Agents Chemother 1993 May; 37(5): 1086–94PubMedCrossRefGoogle Scholar
  213. 213.
    Ng EY, Trucksis M, Hooper DC. Quinolone resistance mediated by norA: physiologic characterization and relationship toflqB, a quinolone resistance locus on the Staphylococcusaureus chromosome. Antimicrob Agents Chemother 1994 Jun; 38(6): 1345–55PubMedCrossRefGoogle Scholar
  214. 214.
    Piddock LJ. Mechanisms of fluoroquinolone resistance: an update 1994–1998. Drugs 1999; 58 Suppl. 2: 11–8CrossRefGoogle Scholar
  215. 215.
    Poole K. Efflux-mediated resistance to fluoroquinolones in gram-negative bacteria. Antimicrob Agents Chemother 2000; 44(9): 2233–41PubMedCrossRefGoogle Scholar
  216. 216.
    Poole K. Efflux-mediated resistance to fluoroquinolones in gram-positive bacteria and the mycobacteria. Antimicrob Agents Chemother 2000; 44(10): 2595–9PubMedCrossRefGoogle Scholar
  217. 217.
    Yu JL, Grinius L, Hooper DC. NorA functions as a multidrug efflux protein in both cytoplasmic membrane vesicles and reconstituted proteoliposomes. J Bacteriol 2002 Mar; 184(5): 1370–7PubMedCrossRefGoogle Scholar
  218. 218.
    Kaatz GW, Seo SM. Inducible NorA-mediated multidrug resistance in Staphylococcusaureus. Antimicrob Agents Chemother 1995 Dec; 39(12): 2650–5PubMedCrossRefGoogle Scholar
  219. 219.
    Fournier B, Truong-Bolduc QC, Zhang X, et al. A mutation in the 5' untranslated region increases stability of norAmRNA, encoding a multidrug resistance transporter of Staphylococcus aureus. J Bacteriol 2001 Apr; 183(7): 2367–71PubMedCrossRefGoogle Scholar
  220. 220.
    Kaatz GW, Seo SM, Foster TJ. Introduction of a norApromoter region mutation into the chromosome of a fluoroquinolone-susceptible strain of Staphylococcusaureususing plasmid integration. Antimicrob Agents Chemother 1999 Sep; 43(9): 2222–4PubMedGoogle Scholar
  221. 221.
    Kaatz GW, Seo SM, O'Brien L, et al. Evidence for the existence of a multidrug efflux transporter distinct from NorA in Staphylococcusaureus. Antimicrob Agents Chemother 2000 May; 44(5): 1404–6PubMedCrossRefGoogle Scholar
  222. 222.
    Munoz-Bellido JL, Alonzo Manzanares M, Martinez Andres JA, et al. Efflux pump-mediated quinolone resistance in Staphylococcusaureusstrains wild type for gyrA, gyrB, grlA, and norA. Antimicrob Agents Chemother 1999 Feb; 43(2): 354–6PubMedGoogle Scholar
  223. 223.
    Piddock LJ, Jin YF, Webber MA, et al. Novel ciprofloxacin-resistant, nalidixic acid-susceptible mutant of Staphylococcus aureus. Antimicrob Agents Chemother 2002 Jul; 46(7): 2276–8PubMedCrossRefGoogle Scholar
  224. 224.
    Noguchi N, Tamura M, Narui K, et al. Frequency and genetic characterization of multidrug-resistant mutants of Staphylococcus aureusafter selection with individual antiseptics and fluoroquinolones. Biol Pharm Bull 2002 Sep; 25(9): 1129–32PubMedCrossRefGoogle Scholar
  225. 225.
    Ross JI, Eady EA, Cove JH, et al. Inducible erythromycin resistance in staphylococci is encoded by a member of the ATP-binding transport super-gene family. Mol Microbiol 1990 Jul; 4(7): 1207–14PubMedCrossRefGoogle Scholar
  226. 226.
    Ross JI, Eady EA, Cove JH, et al. Minimal functional system required for expression of erythromycin resistance by msrAin StaphylococcusaureusRN 4220. Gene 1996 Dec 12; 183(1–2): 143–8PubMedCrossRefGoogle Scholar
  227. 227.
    Leclercq R. Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications. Clin Infect Dis 2002 Feb 15; 34(4): 482–92PubMedCrossRefGoogle Scholar
  228. 228.
    Schmitz FJ, Sadurski R, Kray A, et al. Prevalence of macrolide-resistance genes in Staphylococcusaureusand Enterococcus faeciumisolates from 24 European university hospitals. J Antimicrob Chemother 2000 Jun; 45(6): 891–4PubMedCrossRefGoogle Scholar
  229. 229.
    Schmitz FJ, Perdikouli M, Beeck A, et al. Molecular surveillance of macrolide, tetracycline and quinolone resistance mechanisms in 1191 clinical European Streptococcuspneumoniae isolates. Int J Antimicrob Agents 2001 Nov; 18(5): 433–6PubMedCrossRefGoogle Scholar
  230. 230.
    Broskey J, Coleman K, Gwynn MN, et al. Efflux and target mutations as quinolone resistance mechanisms in clinical isolates of Streptococcuspneumoniae. J Antimicrob Chemother 2000 Apr; 45 Suppl. 1: 95–9CrossRefGoogle Scholar
  231. 231.
    Bast DJ, Low DE, Duncan CL, et al. Fluoroquinolone resistance in clinical isolates of Streptococcuspneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance. Antimicrob Agents Chemother 2000 Nov; 44(11): 3049–54PubMedCrossRefGoogle Scholar
  232. 232.
    Brenwald NP, Gill MJ, Wise R. Prevalence of a putative efflux mechanism among fluoroquinolone-resistant clinical isolates of Streptococcuspneumoniae. Antimicrob Agents Chemother 1998 Aug; 42(8): 2032–5PubMedGoogle Scholar
  233. 233.
    Baranova NN, Neyfakh AA. Apparent involvement of a multidrug transporter in the fluoroquinolone resistance of Streptococcus pneumoniae. Antimicrob Agents Chemother 1997 Jun; 41(6): 1396–8PubMedGoogle Scholar
  234. 234.
    Zeller V, Janoir C, Kitzis MD, et al. Active efflux as a mechanism of resistance to ciprofloxacin in Streptococcus pneumoniae. Antimicrob Agents Chemother 1997 Sep; 41(9): 1973–8PubMedGoogle Scholar
  235. 235.
    Marshall NJ, Piddock LJ. Antibacterial efflux systems. Microbiologia 1997 Sep; 13(3): 285–300PubMedGoogle Scholar
  236. 236.
    Piddock LJ, Jin YF, Everett MJ. Non-gyrA-mediated ciprofloxacin resistance in laboratory mutants of Streptococcuspneumoniae. J Antimicrob Chemother 1997 May; 39(5): 609–15PubMedCrossRefGoogle Scholar
  237. 237.
    Piddock LJ, Johnson MM. Accumulation of 10 fluoroquinolones by wild-type or efflux mutant Streptococcuspneumoniae. Antimicrob Agents Chemother 2002 Mar; 46(3): 813–20PubMedCrossRefGoogle Scholar
  238. 238.
    Piddock LJ, Johnson MM, Simjee S, et al. Expression of efflux pump gene pmrAin fluoroquinolone-resistant and -susceptible clinical isolates of Streptococcuspneumoniae. Antimicrob Agents Chemother 2002 Mar; 46(3): 808–12PubMedCrossRefGoogle Scholar
  239. 239.
    Pestova E, Millichap JJ, Siddiqui F, et al. Non-PmrA-mediated multidrug resistance in Streptococcuspneumoniae. J Antimicrob Chemother 2002 Mar; 49(3): 553–6PubMedCrossRefGoogle Scholar
  240. 240.
    Kataja J, Seppala H, Skurnik M, et al. Different erythromycin resistance mechanisms in group C and group G streptococci. Antimicrob Agents Chemother 1998 Jun; 42(6): 1493–4PubMedGoogle Scholar
  241. 241.
    Sutcliffe J, Tait-Kamradt A, Wondrack L. Streptococcus pneumoniae and p Syogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system. Antimicrob Agents Chemother 1996 Aug; 40(8): 1817–24PubMedGoogle Scholar
  242. 242.
    Widdowson CA, Klugman KP. Molecular mechanisms of resistance to commonly used non-betalactam drugs in Streptococcus pneumoniae. Semin Respir Infect 1999 Sep; 14(3): 255–68PubMedGoogle Scholar
  243. 243.
    French GL. Enterococci and vancomycin resistance. Clin Infect Dis 1998 Aug; 27 Suppl. 1: S75–83PubMedCrossRefGoogle Scholar
  244. 244.
    Moellering Jr RC. Emergence of Enterococcus as a significant pathogen. Clin Infect Dis 1992 Jun; 14(6): 1173–6PubMedCrossRefGoogle Scholar
  245. 245.
    Hallgren A, Abednazari H, Ekdahl C, et al. Antimicrobial susceptibility patterns of enterococci in intensive care units in Sweden evaluated by different MIC breakpoint systems. J Antimicrob Chemother 2001 Jul; 48(1): 53–62PubMedCrossRefGoogle Scholar
  246. 246.
    Neyfakh AA. The ostensible paradox of multidrug recognition. J Mol Microbiol Biotechnol 2001 Apr; 3(2): 151–4PubMedGoogle Scholar
  247. 247.
    Godsey MH, Baranova NN, Neyfakh AA, et al. Crystal structure of MtaN, a global multidrug transporter gene activator. J Biol Chem 2001 Dec 14; 276(50): 47178–84PubMedCrossRefGoogle Scholar
  248. 248.
    Heldwein EE, Brennan RG. Crystal structure of the transcription activator BmrR bound to DNA and a drug. Nature 2001 Jan 18; 409(6818): 378–82PubMedCrossRefGoogle Scholar
  249. 249.
    Neyfakh AA. The multidrug efflux transporter of Bacillussubtilis is a structural and functional homolog of the Staphylococcus NorA protein. Antimicrob Agents Chemother 1992 Feb; 36(2): 484–5PubMedCrossRefGoogle Scholar
  250. 250.
    Poelarends GJ, Mazurkiewicz P, Konings WN. Multidrug transporters and antibiotic resistance in Lactococcuslactis. Biochim Biophys Acta 2002 Sep 10; 1555(1–3): 1–7PubMedGoogle Scholar
  251. 251.
    van Veen HW, Putman M, Margolles A, et al. Molecular pharmacological characterization of two multidrug transporters in Lactococcuslactis. Pharmacol Ther 2000 Mar; 85(3): 245–9PubMedCrossRefGoogle Scholar
  252. 252.
    van Veen HW, Venema K, Bolhuis H, et al. Multidrug resistance mediated by a bacterial homolog of the human multidrug transporter MDR 1. Proc Natl Acad Sci U S A 1996 Oct 1; 93(20): 10668–72PubMedCrossRefGoogle Scholar
  253. 253.
    van Veen HW, Margolles A, Muller M, et al. The homodimeric ATP-binding cassette transporter LmrA mediates multidrug transport by an alternating two-site (two-cylinder engine) mechanism. EMBO J 2000 Jun 1; 19(11): 2503–14PubMedCrossRefGoogle Scholar
  254. 254.
    Poelarends GJ, Konings WN. The transmembrane domains of the ABC multidrug transporter LmrA form a cytoplasmic exposed, aqueous chamber within the membrane. J Biol Chem 2002 Nov 8; 277(45): 42891–8PubMedCrossRefGoogle Scholar
  255. 255.
    van Veen HW, Callaghan R, Soceneantu L, et al. A bacterial antibiotic-resistance gene that complements the human multidrug-resistance P-glycoprotein gene. Nature 1998 Jan 15; 391(6664): 291–5PubMedCrossRefGoogle Scholar
  256. 256.
    Hofmeyr JH, Rohwer JM, Snoep JL, et al. How to distinguish between the vacuum cleaner and flippase mechanisms of the LmrA multi-drug transporter in Lactococcuslactis. Mol Biol Rep 2002; 29(1–2): 107–12PubMedCrossRefGoogle Scholar
  257. 257.
    Putman M, Van Veen HW, Degener JE, et al. Antibiotic resistance: era of the multidrug pump. Mol Microbiol 2000 May; 36(3): 772–3PubMedCrossRefGoogle Scholar
  258. 258.
    Putman M, Koole LA, van Veen HW, et al. The secondary multidrug transporter LmrP contains multiple drug interaction sites. Biochemistry 1999 Oct 19; 38(42): 13900–5PubMedCrossRefGoogle Scholar
  259. 259.
    Putman M, van Veen HW, Degener JE, et al. The lactococcal secondary multidrug transporter LmrP confers resistance to lincosamides, macrolides, streptogramins and tetracyclines. Microbiology 2001 Oct; 147 (Pt 10): 2873–80PubMedGoogle Scholar
  260. 260.
    Dye C, Scheele S, Dolin P, et al. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO global surveillance and monitoring project. JAMA 1999; 282(7): 677–86Google Scholar
  261. 261.
    Jarlier V, Nikaido H. Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol Lett 1994 Oct 15; 123(1–2): 11–8PubMedCrossRefGoogle Scholar
  262. 262.
    Trias J, Benz R. Permeability of the cell wall of Mycobacterium smegmatis. Mol Microbiol 1994 Oct; 14(2): 283–90PubMedCrossRefGoogle Scholar
  263. 263.
    Engelhardt H, Heinz C, Niederweis M. A tetrameric porin limits the cell wall permeability of Mycobacteriumsmegmatis. J Biol Chem 2002 Oct 4; 277(40): 37567–72PubMedCrossRefGoogle Scholar
  264. 264.
    Brennan PJ, Nikaido H. The envelope of mycobacteria. Annu Rev Biochem 1995; 64: 29–63PubMedCrossRefGoogle Scholar
  265. 265.
    Liu J, Takiff HE, Nikaido H. Active efflux of fluoroquinolones in Mycobacteriumsmegmatismediated by LfrA, a multidrug efflux pump. J Bacteriol 1996 Jul; 178(13): 3791–5PubMedGoogle Scholar
  266. 266.
    Sander P, De Rossi E, Boddinghaus B, et al. Contribution of the multidrug efflux pump LfrA to innate mycobacterial drug resistance. FEMS Microbiol Lett 2000 Dec 1; 193(1): 19–23PubMedCrossRefGoogle Scholar
  267. 267.
    Wilson M, DeRisi J, Kristensen HH, et al. Exploring drug-induced alterations in gene expression in Mycobacteriumtuberculosis by microarray hybridization. Proc Natl Acad Sci U S A 1999 Oct 26; 96(22): 12833–8PubMedCrossRefGoogle Scholar
  268. 268.
    Viveiros M, Portugal I, Bettencourt R, et al. Isoniazid-induced transient high-level resistance in Mycobacteriumtuberculosis. Antimicrob Agents Chemother 2002 Sep; 46(9): 2804–10PubMedCrossRefGoogle Scholar
  269. 269.
    Zhang Y, Scorpio A, Nikaido H, et al. Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacteriumtuberculosisto pyrazinamide. J Bacteriol 1999 Apr; 181(7): 2044–9PubMedGoogle Scholar
  270. 270.
    Schaller A, Guo M, Gisanrin O, et al. Escherichiacoligenes involved in resistance to pyrazinoic acid, the active component of the tuberculosis drug pyrazinamide. FEMS Microbiol Lett 2002 Jun 4; 211(2): 265–70PubMedCrossRefGoogle Scholar
  271. 271.
    Piddock LJ, Williams KJ, Ricci V. Accumulation of rifampicin by Mycobacteriumaurum, Mycobacteriumsmegmatisand Mycobacterium tuberculosis. J Antimicrob Chemother 2000 Feb; 45(2): 159–65PubMedCrossRefGoogle Scholar
  272. 272.
    Hui J, Gordon N, Kajioka R. Permeability barrier to rifampin in mycobacteria. Antimicrob Agents Chemother 1977 May; 11(5): 773–9PubMedCrossRefGoogle Scholar
  273. 273.
    Li XZ, Wang YS, He ZN. Alteration of permeability of bacterial envelope barrier in rifamdin-resistant Mycobacteriumtuberculosis [in Chinese]. Hua Xi Yi Ke Da Xue Xue Bao 1988 Dec; 19(4): 388–91PubMedGoogle Scholar
  274. 274.
    Braibant M, Gilot P, Content J. The ATP binding cassette (ABC) transport systems of Mycobacteriumtuberculosis. FEMS Microbial Rev 2000; 24(4): 449–67CrossRefGoogle Scholar
  275. 275.
    Kaur P, Russell J. Biochemical coupling between the DrrA and DrrB proteins of the doxorubicin efflux pump of Streptomyces peucetius. J Biol Chem 1998 Jul 10; 273(28): 17933–9PubMedCrossRefGoogle Scholar
  276. 276.
    Guilfoile PG, Hutchinson CR. A bacterial analog of the mdr gene of mammalian tumor cells is present in Streptomyces peucetius, the producer of daunorubicin and doxorubicin. Proc Natl Acad Sci U S A 1991 Oct 1; 88(19): 8553–7PubMedCrossRefGoogle Scholar
  277. 277.
    Banerjee SK, Bhatt K, Misra P, et al. Involvement of a natural transport system in the process of efflux-mediated drug resistance in Mycobacteriumsmegmatis. Mol Gen Genet 2000 Jan; 262(6): 949–56PubMedCrossRefGoogle Scholar
  278. 278.
    Bhatt K, Banerjee SK, Chakraborti PK. Evidence that phosphate specific transporter is amplified in a fluoroquinolone resistant Mycobacteriumsmegmatis. Eur J Biochem 2000 Jul; 267(13): 4028–32PubMedCrossRefGoogle Scholar
  279. 279.
    Reizer J, Reizer A, Saier Jr MH. A new subfamily of bacterial ABC-type transport systems catalyzing export of drugs and carbohydrates. Protein Sci 1992 Oct; 1(10): 1326–32PubMedCrossRefGoogle Scholar
  280. 280.
    Ninio S, Rotem D, Schuldiner S. Functional analysis of novel multidrug transporters from human pathogens. J Biol Chem 2001 Dec 21; 276(51): 48250–6PubMedGoogle Scholar
  281. 281.
    Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacteriumtuberculosis: 1998 update. Tuber Lung Dis 1998; 79(1): 3–29PubMedCrossRefGoogle Scholar
  282. 282.
    Zheleznova EE, Markham PN, Neyfakh AA, et al. Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter. Cell 1999 Feb 5; 96(3): 353–62PubMedCrossRefGoogle Scholar
  283. 283.
    Vazquez-Laslop N, Markham PN, Neyfakh AA. Mechanism of ligand recognition by BmrR, the multidrug-responding transcriptional regulator: mutational analysis of the ligand-binding site. Biochemistry 1999 Dec 21; 38(51): 16925–31PubMedCrossRefGoogle Scholar
  284. 284.
    Schumacher MA, Miller MC, Grkovic S, et al. Structural mechanisms of QacR induction and multidrug recognition. Science 2001 Dec 7; 294(5549): 2158–63PubMedCrossRefGoogle Scholar
  285. 285.
    Schumacher MA, Brennan RG. Structural mechanisms of multidrug recognition and regulation by bacterial multidrug transcription factors. Mol Microbiol 2002 Aug; 45(4): 885–93PubMedCrossRefGoogle Scholar
  286. 286.
    Neyfakh AA. Mystery of multidrug transporters: the answer can be simple. Mol Microbiol 2002 Jun; 44(5): 1123–30PubMedCrossRefGoogle Scholar
  287. 287.
    Vincent F, Spinelli S, Ramoni R, et al. Complexes of porcine odorant binding protein with odorant molecules belonging to different chemical classes. J Mol Biol 2000 Jun 30; 300(1): 127–39PubMedCrossRefGoogle Scholar
  288. 288.
    Murakami S, Nakashima R, Yamashita E, et al. Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 2002 Oct 10; 419(6907): 587–93PubMedCrossRefGoogle Scholar
  289. 289.
    Fujihira E, Tamura N, Yamaguchi A. Membrane topology of a multidrug efflux transporter, AcrB, in Escherichiacoli. J Biochem (Tokyo) 2002 Jan; 131(1): 145–51CrossRefGoogle Scholar
  290. 290.
    Gotoh N, Kusumi T, Tsujimoto H, et al. Topological analysis of an RND family transporter, MexD of Pseudomonasaeruginosa. FEBS Lett 1999 Sep 10; 458(1): 32–6PubMedCrossRefGoogle Scholar
  291. 291.
    Guan L, Ehrmann M, Yoneyama H, et al. Membrane topology of the xenobiotic-exporting subunit, MexB, of the MexA,B-OprM extrusion pump in Pseudomonasaeruginosa. J Biol Chem 1999 Apr 9; 274(15): 10517–22PubMedCrossRefGoogle Scholar
  292. 292.
    Yoneyama H, Ocaktan A, Gotoh N, et al. Subunit swapping in the Mex-extrusion pumps in Pseudomonasaeruginosa. Biochem Biophys Res Commun 1998 Mar 27; 244(3): 898–902PubMedCrossRefGoogle Scholar
  293. 293.
    Tikhonova EB, Wang Q, Zgurskaya HI. Chimeric analysis of the multicomponent multidrug efflux transporters from gramnegative bacteria. J Bacteriol 2002 Dec; 184(23): 6499–507PubMedCrossRefGoogle Scholar
  294. 294.
    Mao W, Warren MS, Black DS, et al. On the mechanism of substrate specificity by resistance nodulation division (RND)-type multidrug resistance pumps: the large periplasmic loops of MexD from Pseudomonasaeruginosaare involved in substrate recognition. Mol Microbiol 2002 Nov; 46(3): 889–901PubMedCrossRefGoogle Scholar
  295. 295.
    Yu EW, McDermott G, Zgurskaya HI, et al. Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 2003; 300(5621): 976–80PubMedCrossRefGoogle Scholar
  296. 296.
    Yu EW, Aires JR, Nikaido H. AcrB multidrug efflux pump of Escherichiacoli: composite substrate-binding cavity of exceptional flexibility generates its extremely wide substrate specificity. J Bacteriol 2003; 185(19): 5657–64PubMedCrossRefGoogle Scholar
  297. 297.
    Goldberg M, Pribyl T, Juhnke S, et al. Energetics and topology of CzcA, a cation/proton antiporter of the resistance-nodulation-cell division protein family. J Biol Chem 1999 Sep 10; 274(37): 26065–70PubMedCrossRefGoogle Scholar
  298. 298.
    Guan L, Nakae T. Identification of essential charged residues in transmembrane segments of the multidrug transporter MexB of Pseudomonasaeruginosa. J Bacteriol 2001 Mar; 183(5): 1734–9PubMedCrossRefGoogle Scholar
  299. 299.
    Aires JR, Pechere JC, Van Delden C, et al. Amino acid residues essential for function of the MexF efflux pump protein of Pseudomonasaeruginosa. Antimicrob Agents Chemother 2002 Jul; 46(7): 2169–73PubMedCrossRefGoogle Scholar
  300. 300.
    Zgurskaya HI, Nikaido H. AcrA is a highly asymmetric protein capable of spanning the periplasm. J Mol Biol 1999 Jan 8; 285(1): 409–20PubMedCrossRefGoogle Scholar
  301. 301.
    Zgurskaya HI, Nikaido H. Cross-linked complex between oligomeric periplasmic lipoprotein AcrA and the inner-membrane-associated multidrug efflux pump AcrB from Escherichia coli. J Bacteriol 2000 Aug; 182(15): 4264–7PubMedCrossRefGoogle Scholar
  302. 302.
    Avila-Sakar AJ, Misaghi S, Wilson-Kubalek EM, et al. Lipid-layer crystallization and preliminary three-dimensional structural analysis of AcrA, the periplasmic component of a bacterial multidrug efflux pump. J Struct Biol 2001 Oct; 136(1): 81–8PubMedCrossRefGoogle Scholar
  303. 303.
    Hayashi S, Wu HC. Lipoproteins in bacteria. J Bioenerg Biomembr 1990 Jun; 22(3): 451–71PubMedCrossRefGoogle Scholar
  304. 304.
    Seiffer D, Klein JR, Plapp R. EnvC, a new lipoprotein of the cytoplasmic membrane of Escherichiacoli. FEMS Microbiol Lett 1993 Mar 1; 107(2–3): 175–8PubMedCrossRefGoogle Scholar
  305. 305.
    Yoneyama H, Maseda H, Kamiguchi H, et al. Function of the membrane fusion protein, MexA, of the MexA,B-OprM efflux pump in Pseudomonasaeruginosawithout an anchoring membrane. J Biol Chem 2000 Feb 18; 275(7): 4628–34PubMedCrossRefGoogle Scholar
  306. 306.
    Zgurskaya HI, Nikaido H. Multidrug resistance mechanisms: drug efflux across two membranes. Mol Microbiol 2000 Jul; 37(2): 219–25PubMedCrossRefGoogle Scholar
  307. 307.
    Hwang J, Tai PC. Mutational analysis of CvaA in the highly conserved domain of the membrane fusion protein family. Curr Microbiol 1999 Oct; 39(4): 195–9PubMedCrossRefGoogle Scholar
  308. 308.
    Hwang J, Zhong X, Tai PC. Interactions of dedicated export membrane proteins of the colicin V secretion system: CvaA, a member of the membrane fusion protein family, interacts with CvaB and TolC. J Bacteriol 1997 Oct; 179(20): 6264–70PubMedGoogle Scholar
  309. 309.
    Pimenta AL, Young J, Holland IB, et al. Antibody analysis of the localisation, expression and stability of HlyD, the MFP component of the E. colihaemolysin translocator. Mol Gen Genet 1999 Feb; 261(1): 122–32PubMedCrossRefGoogle Scholar
  310. 310.
    Koronakis V, Sharff A, Koronakis E, et al. Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature 2000 Jun 22; 405(6789): 914–9PubMedCrossRefGoogle Scholar
  311. 311.
    Andersen C, Hughes C, Koronakis V. Chunnel vision: export and efflux through bacterial channel-tunnels. EMBO Rep 2000 Oct; 1(4): 313–8PubMedCrossRefGoogle Scholar
  312. 312.
    Wong KK, Brinkman FS, Benz RS, et al. Evaluation of a structural model of Pseudomonasaeruginosaouter membrane protein OprM, an efflux component involved in intrinsic antibiotic resistance. J Bacteriol 2001 Jan; 183(1): 367–74PubMedCrossRefGoogle Scholar
  313. 313.
    Li XZ, Poole K. Mutational analysis of the OprM outer membrane component of the MexA-MexB-OprM multidrug efflux system of Pseudomonasaeruginosa. J Bacteriol 2001 Jan; 183(1): 12–27PubMedCrossRefGoogle Scholar
  314. 314.
    Nakajima A, Sugimoto Y, Yoneyama H, et al. Localization of the outer membrane subunit OprM of resistance-nodulation-cell division family multicomponent efflux pump in Pseudomonas aeruginosa. J Biol Chem 2000 Sep 29; 275(39): 30064–8PubMedCrossRefGoogle Scholar
  315. 315.
    Benz R, Maier E, Gentschev I. TolC of Escherichiacolifunctions as an outer membrane channel. Zentralbl Bakteriol 1993 Apr; 278(2–3): 187–96PubMedCrossRefGoogle Scholar
  316. 316.
    Wong KK, Hancock RE. Insertion mutagenesis and membrane topology model of the Pseudomonasaeruginosaouter membrane protein OprM. J Bacteriol 2000 May; 182(9): 2402–10PubMedCrossRefGoogle Scholar
  317. 317.
    Yoshihara E, Maseda H, Saito K. The outer membrane component of the multidrug efflux pump from Pseudomonasaeruginosa may be a gated channel. Eur J Biochem 2002 Oct; 269(19): 4738–45PubMedCrossRefGoogle Scholar
  318. 318.
    Postle K. TonB protein and energy transduction between membranes. J Bioenerg Biomembr 1993 Dec; 25(6): 591–601PubMedGoogle Scholar
  319. 319.
    Zhao Q, Li XZ, Mistry A, et al. Influence of the TonB energy-coupling protein on efflux-mediated multidrug resistance in Pseudomonasaeruginosa. Antimicrob Agents Chemother 1998 Sep; 42(9): 2225–31PubMedGoogle Scholar
  320. 320.
    Godoy P, Ramos-Gonzalez MI, Ramos JL. Involvement of the TonB system in tolerance to solvents and drugs in Pseudomonas putidaDOT-T1E. J Bacteriol 2001 Sep; 183(18): 5285–92PubMedCrossRefGoogle Scholar
  321. 321.
    Rouquette-Loughlin C, Stojiljkovic I, Hrobowski T, et al. Inducible, but not constitutive, resistance of gonococci to hydrophobic agents due to the MtrC-MtrD-MtrE efflux pump requires TonB-ExbB-ExbD proteins. Antimicrob Agents Chemother 2002 Feb; 46(2): 561–5PubMedCrossRefGoogle Scholar
  322. 322.
    Maseda H, Kitao M, Eda S, et al. A novel assembly process of the multicomponent xenobiotic efflux pump in Pseudomonas aeruginosa. Mol Microbiol 2002 Nov; 46(3): 677–86PubMedCrossRefGoogle Scholar
  323. 323.
    Helling RB, Janes BK, Kimball H, et al. Toxic waste disposal in Escherichiacoli. J Bacteriol 2002 Jul; 184(13): 3699–703PubMedCrossRefGoogle Scholar
  324. 324.
    Grkovic S, Brown MH, Skurray RA. Regulation of bacterial drug export systems. Microbiol Mol Biol Rev 2002 Dec; 66(4): 671–701PubMedCrossRefGoogle Scholar
  325. 325.
    Ma D, Alberti M, Lynch C, et al. The local repressor AcrR plays a modulating role in the regulation of acrABgenes of Escherichia coliby global stress signals. Mol Microbiol 1996 Jan; 19(1): 101–12PubMedCrossRefGoogle Scholar
  326. 326.
    Orth P, Schnappinger D, Hillen W, et al. Structural basis of gene regulation by the tetracycline inducible Tet repressor-operator system. Nat Struct Biol 2000 Mar; 7(3): 215–9PubMedCrossRefGoogle Scholar
  327. 327.
    Orth P, Cordes F, Schnappinger D, et al. Conformational changes of the Tet repressor induced by tetracycline trapping. J Mol Biol 1998 Jun 5; 279(2): 439–47PubMedCrossRefGoogle Scholar
  328. 328.
    Bochner BR, Huang HC, Schieven GL, et al. Positive selection for loss of tetracycline resistance. J Bacteriol 1980 Aug; 143(2): 926–33PubMedGoogle Scholar
  329. 329.
    Masuda N, Sakagawa E, Ohya S, et al. Contribution of the MexX-MexY-OprM efflux system to intrinsic resistance in Pseudomonasaeruginosa. Antimicrob Agents Chemother 2000 Sep; 44(9): 2242–6PubMedCrossRefGoogle Scholar
  330. 330.
    Duque E, Segura A, Mosqueda G, et al. Global and cognate regulators control the expression of the organic solvent efflux pumps TtgABC and TtgDEF of Pseudomonasputida. Mol Microbiol 2001 Feb; 39(4): 1100–6PubMedCrossRefGoogle Scholar
  331. 331.
    Lomovskaya O, Lewis K, Matin A. EmrR is a negative regulator of the Escherichiacolimultidrug resistance pump EmrAB. J Bacteriol 1995 May; 177(9): 2328–34PubMedGoogle Scholar
  332. 332.
    Lomovskaya O, Kawai F, Matin A. Differential regulation of the mcband emroperons of Escherichiacoli: role of mcbin multidrug resistance. Antimicrob Agents Chemother 1996 Apr; 40(4): 1050–2PubMedGoogle Scholar
  333. 333.
    Relia M, Haas D. Resistance of PseudomonasaeruginosaPAO to nalidixic acid and low levels of β-lactam antibiotics: mapping of chromosomal genes. Antimicrob Agents Chemother 1982 Aug; 22(2): 242–9CrossRefGoogle Scholar
  334. 334.
    Adewoye L, Sutherland A, Srikumar R, et al. The MexR repressor of the MexAB-OprM multidrug efflux operon in Pseudomonasaeruginosa:characterization of mutations compromising activity. J Bacteriol 2002 Aug; 184(15): 4308–12PubMedCrossRefGoogle Scholar
  335. 335.
    Saito K, Yoneyama H, Nakae T. nalB-type mutations causing the overexpression of the MexAB-OprM efflux pump are located in the mexRgene of the Pseudomonasaeruginosa chromosome. FEMS Microbiol Lett 1999 Oct 1; 179(1): 67–72PubMedCrossRefGoogle Scholar
  336. 336.
    Jalal S, Wretlind B. Mechanisms of quinolone resistance in clinical strains of Pseudomonasaeruginosa. Microb Drug Resist 1998 Winter; 4(4): 257–61PubMedCrossRefGoogle Scholar
  337. 337.
    Evans K, Adewoye L, Poole K. MexR repressor of the MexAB-OprM multidrug efflux operon of Pseudomonasaeruginosa: identification of MexR binding sites in the MexA-MexR intergenic region. J Bacteriol 2001 Feb; 183(3): 807–12PubMedCrossRefGoogle Scholar
  338. 338.
    Lim D, Poole K, Strynadka NC. Crystal structure of the MexR repressor of the mexRAB-oprMmultidrug efflux operon of Pseudomonasaeruginosa. J Biol Chem 2002 Aug 9; 277(32): 29253–9PubMedCrossRefGoogle Scholar
  339. 339.
    Alekshun MN, Levy SB, Mealy TR, et al. The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 Å resolution. Nat Struct Biol 2001 Aug; 8(8): 710–4PubMedCrossRefGoogle Scholar
  340. 340.
    Cao L, Srikumar R, Poole K. Identification and characterization of nalCmultidrug-resistant isolates of Pseudomonasaeruginosa [abstract no. C1-430]. Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Washington, DC; 2002 Sep 27–30, San Diego (CA), 29Google Scholar
  341. 341.
    Weickert MJ, Adhya S. A family of bacterial regulators homologous to Gal and Lac repressors. J Biol Chem 1992 Aug 5; 267(22): 15869–74PubMedGoogle Scholar
  342. 342.
    Shiba T, Ishiguro K, Takemoto N, et al. Purification and characterization of the PseudomonasaeruginosaNfxB protein, the negative regulator of the nfxBgene. J Bacteriol 1995 Oct; 177(20): 5872–7PubMedGoogle Scholar
  343. 343.
    Köhler T, Epp SF, Curty LK, et al. Characterization of MexT, the regulator of the MexE-MexF-OprN multidrug efflux system of Pseudomonasaeruginosa. J Bacteriol 1999 Oct; 181(20): 6300–5PubMedGoogle Scholar
  344. 344.
    Schell MA. Molecular biology of the LysR family of transcriptional regulators. Annu Rev Microbiol 1993; 47: 597–626PubMedCrossRefGoogle Scholar
  345. 345.
    Grkovic S, Brown MH, Roberts NJ, et al. QacR is a repressor protein that regulates expression of the Staphylococcusaureus multidrug efflux pump QacA. J Biol Chem 1998 Jul 17; 273(29): 18665–73PubMedCrossRefGoogle Scholar
  346. 346.
    Stock AM, Robinson VL, Goudreau PN. Two-component signal transduction. Annu Rev Biochem 2000; 69: 183–215PubMedCrossRefGoogle Scholar
  347. 347.
    Kieboom J, Dennis JJ, Zylstra GJ, et al. Active efflux of organic solvents by PseudomonasputidaS12 is induced by solvents. J Bacteriol 1998 Dec; 180(24): 6769–72PubMedGoogle Scholar
  348. 348.
    Alekshun MN, Levy SB. Regulation of chromosomally mediated multiple antibiotic resistance: the marregulon. Antimicrob Agents Chemother 1997 Oct; 41(10): 2067–75PubMedGoogle Scholar
  349. 349.
    Martin RG, Rosner JL. Binding of purified multiple antibiotic-resistance repressor protein (MarR) to maroperator sequences. Proc Natl Acad Sci U S A 1995 Jun 6; 92(12): 5456–60PubMedCrossRefGoogle Scholar
  350. 350.
    Seoane AS, Levy SB. Characterization of MarR, the repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli. J Bacteriol 1995 Jun; 177(12): 3414–9PubMedGoogle Scholar
  351. 351.
    Gallegos MT, Michan C, Ramos JL. The XylS/AraC family of regulators. Nucleic Acids Res 1993 Feb 25; 21(4): 807–10PubMedCrossRefGoogle Scholar
  352. 352.
    Barbosa TM, Levy SB. Differential expression of over 60 chromosomal genes in Escherichiacoliby constitutive expression of MarA. J Bacteriol 2000 Jun; 182(12): 3467–74PubMedCrossRefGoogle Scholar
  353. 353.
    Okusu H, Ma D, Nikaido H. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichiacoli multiple-antibiotic-resistance (Mar) mutants. J Bacteriol 1996 Jan; 178(1): 306–8PubMedGoogle Scholar
  354. 354.
    Li H, Park JT. The periplasmic murein peptide-binding protein MppA is a negative regulator of multiple antibiotic resistance in Escherichiacoli. J Bacteriol 1999 Aug; 181(16): 4842–7PubMedGoogle Scholar
  355. 355.
    Ma D, Cook DN, Alberti M, et al. Genes acrAand acrBencode a stress-induced efflux system of Escherichiacoli. Mol Microbiol 1995 Apr; 16(1): 45–55PubMedCrossRefGoogle Scholar
  356. 356.
    McMurry LM, Oethinger M, Levy SB. Overexpression of marA, soxS, or acrABproduces resistance to triclosan in laboratory and clinical strains of Escherichiacoli. FEMS Microbiol Lett 1998 Sep 15; 166(2): 305–9PubMedCrossRefGoogle Scholar
  357. 357.
    White DG, Goldman JD, Demple B, et al. Role of the acrAB locus in organic solvent tolerance mediated by expression of marA, soxS, or robAin Escherichiacoli. J Bacteriol 1997 Oct; 179(19): 6122–6PubMedGoogle Scholar
  358. 358.
    Hidalgo E, Ding H, Demple B. Redox signal transduction via iron-sulfur clusters in the SoxR transcription activator. Trends Biochem Sci 1997 Jun; 22(6): 207–10PubMedCrossRefGoogle Scholar
  359. 359.
    Kwon HJ, Bennik MH, Demple B, etal. Crystal structure of the Escherichia coliRob transcription factor in complex with DNA. Nat Struct Biol 2000 May; 7(5): 424–30PubMedCrossRefGoogle Scholar
  360. 360.
    Nakajima H, Kobayashi K, Kobayashi M, etal. Overexpression of the robAgene increases organic solvent tolerance and multiple antibiotic and heavy metal ion resistance in Escherichia coli. Appl Environ Microbiol 1995 Jun; 61(6): 2302–7PubMedGoogle Scholar
  361. 361.
    Ariza RR, Li Z, Ringstad N, et al. Activation of multiple antibiotic resistance and binding of stress-inducible promoters by Escherichia coliRob protein. J Bacteriol 1995 Apr; 177(7): 1655–61PubMedGoogle Scholar
  362. 362.
    Jair KW, Yu X, Skarstad K, et al. Transcriptional activation of promoters of the Superoxide and multiple antibiotic resistance regulons by Rob, a binding protein of the Escherichia coli origin of chromosomal replication. J Bacteriol 1996 May; 178(9): 2507–13PubMedGoogle Scholar
  363. 363.
    Rosenberg EY, Bertenthal D, Nilles ML, et al. Bile salts and fatty acids induce the expression of Escherichia coliAcrAB multidrug efflux pump through their interaction with Rob regulatory protein. Mol Microbiol 2003; 48(6): 1609–19PubMedCrossRefGoogle Scholar
  364. 364.
    Aono R, Tsukagoshi N, Yamamoto M. Involvement of outer membrane protein TolC, a possible member of the mar-sox regulon, in maintenance and improvement of organic solvent tolerance of Escherichia coliK-12. J Bacteriol 1998 Feb; 180(4): 938–44PubMedGoogle Scholar
  365. 365.
    Cohen SP, McMurry LM, Levy SB. marAlocus causes decreased expression of OmpF porin in multiple-antibiotic-resistant (Mar) mutants of Escherichia coli. J Bacteriol 1988 Dec; 170(12): 5416–22PubMedGoogle Scholar
  366. 366.
    Rosner JL, Chai TJ, Foulds J. Regulation of ompFporin expression by salicylate in Escherichia coli. J Bacteriol 1991 Sep; 173(18): 5631–8PubMedGoogle Scholar
  367. 367.
    Nikaido H, Rosenberg EY, Foulds J. Porin channels in Escherichia coli: studies with β-lactams in intact cells. J Bacteriol 1983 Jan; 153(1): 232–40PubMedGoogle Scholar
  368. 368.
    Nikaido H, Rosenberg EY. Porin channels in Escherichiacoli: studies with liposomes reconstituted from purified proteins. J Bacteriol 1983 Jan; 153(1): 241–52PubMedGoogle Scholar
  369. 369.
    Rahmati S, Yang S, Davidson AL, et al. Control of the AcrAB multidrug efflux pump by quorum-sensing regulator SdiA. Mol Microbiol 2002 Feb; 43(3): 677–85PubMedCrossRefGoogle Scholar
  370. 370.
    George AM, Hall RM, Stokes HW. Multidrug resistance in Klebsiellapneumoniae: a novel gene, ramA, confers a multidrug resistance phenotype in Escherichia coli. Microbiology 1995 Aug; 141 (Pt 8): 1909–20PubMedCrossRefGoogle Scholar
  371. 371.
    Vaara M. Antibiotic-supersusceptible mutants of Escherichia coliand Salmonellatyphimurium. Antimicrob Agents Chemother 1993 Nov; 37(11): 2255–60PubMedCrossRefGoogle Scholar
  372. 372.
    Mazzariol A, Cornaglia G, Nikaido H. Contributions of the AmpC β-lactamase and the AcrAB multidrug efflux system in intrinsic resistance of Escherichia coliK-12 to β-lactams. Antimicrob Agents Chemother 2000 May; 44(5): 1387–90PubMedCrossRefGoogle Scholar
  373. 373.
    Cho D, Blais J, Tangen K, et al. Prevalence of efflux pumpsamong clinical isolates of fluoroquinolone-resistant Pseudomonas aeruginosa[abstract no. 1267]. Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, DC; 1999 Sep 26–29; San Francisco (CA), 327Google Scholar
  374. 374.
    George AM, Levy SB. Amplifiable resistance to tetracycline, chloramphenicol, and other antibiotics in Escherichiacoli: involvement of a non-plasmid-determined efflux of tetracycline. J Bacteriol 1983 Aug; 155(2): 531–40PubMedGoogle Scholar
  375. 375.
    George AM, Levy SB. Gene in the major cotransduction gap of the Escherichia coliK-12 linkage map required for the expression of chromosomal resistance to tetracycline and other antibiotics. J Bacteriol 1983 Aug; 155(2): 541–8PubMedGoogle Scholar
  376. 376.
    Russell AD. Do biocides select for antibiotic resistance? J Pharm Pharmacol 2000 Feb; 52(2): 227–33PubMedCrossRefGoogle Scholar
  377. 377.
    Cohen SP, Levy SB, Foulds J, et al. Salicylate induction of antibiotic resistance in Escherichia coli:activation of the mar operon and a mar-independent pathway. J Bacteriol 1993 Dec; 175(24): 7856–62PubMedGoogle Scholar
  378. 378.
    Sumita Y, Fukasawa M. Transient carbapenem resistance induced by salicylate in Pseudomonasaeruginosaassociated with suppression of outer membrane protein D2 synthesis. Antimicrob Agents Chemother 1993 Dec; 37(12): 2743–6PubMedCrossRefGoogle Scholar
  379. 379.
    Burns JL, Clark DK. Salicylate-inducible antibiotic resistance in Pseudomonascepaciaassociated with absence of a poreforming outer membrane protein. Antimicrob Agents Chemother 1992 Oct; 36(10): 2280–5PubMedCrossRefGoogle Scholar
  380. 380.
    Domenico P, Hopkins T, Cunha BA. The effect of sodium salicylate on antibiotic susceptibility and synergy in Klebsiella pneumoniae. J Antimicrob Chemother 1990 Sep; 26(3): 343–51PubMedCrossRefGoogle Scholar
  381. 381.
    Schaller A, Sun Z, Yang Y, et al. Salicylate reduces susceptibility of Mycobacteriumtuberculosisto multiple antituberculosis drugs. Antimicrob Agents Chemother 2002 Aug; 46(8): 2636–9PubMedCrossRefGoogle Scholar
  382. 382.
    Price CT, O'Brien FG, Shelton BP, et al. Effects of salicylate and related compounds on fusidic acid MICs in Staphylococcus aureus. J Antimicrob Chemother 1999 Jul; 44(1): 57–64PubMedCrossRefGoogle Scholar
  383. 383.
    Gustafson JE, Candelaria PV, Fisher SA, et al. Growth in the presence of salicylate increases fluoroquinolone resistance in Staphylococcusaureus. Antimicrob Agents Chemother 1999 Apr; 43(4): 990–2PubMedGoogle Scholar
  384. 384.
    Price CT, Kaatz GW, Gustafson JE. The multidrug efflux pump NorA is not required for salicylate-induced reduction in drug accumulation by Staphylococcusaureus. Int J Antimicrob Agents 2002 Sep; 20(3): 206–13PubMedCrossRefGoogle Scholar
  385. 385.
    Williams RJ, Livermore DM, Lindridge MA, et al. Mechanisms of β-lactam resistance in British isolates of Pseudomonas aeruginosa. J Med Microbiol 1984 Jun; 17(3): 283–93PubMedCrossRefGoogle Scholar
  386. 386.
    Bert F, Lambert-Zechovsky N. Comparative distribution of resistance patterns and serotypes in Pseudomonasaeruginosa isolates from intensive care units and other wards. J Antimicrob Chemother 1996 Apr; 37(4): 809–13PubMedCrossRefGoogle Scholar
  387. 387.
    Jakics EB, Iyobe S, Hirai K, et al. Occurrence of the nfxBtype mutation in clinical isolates of Pseudomonasaeruginosa. Antimicrob Agents Chemother 1992 Nov; 36(11): 2562–5PubMedCrossRefGoogle Scholar
  388. 388.
    Fukuda H, Hosaka M, Iyobe S, et al. nfxC-type quinolone resistance in a clinical isolate of Pseudomonasaeruginosa. Antimicrob Agents Chemother 1995 Mar; 39(3): 790–2PubMedCrossRefGoogle Scholar
  389. 389.
    Beinlich KL, Chuanchuen R, Schweizer HP. Contribution of multidrug efflux pumps to multiple antibiotic resistance in veterinary clinical isolates of Pseudomonasaeruginosa. FEMS Microbiol Lett 2001 May 1; 198(2): 129–34PubMedCrossRefGoogle Scholar
  390. 390.
    Hoiby N. New antimicrobials in the management of cystic fibrosis. J Antimicrob Chemother 2002 Feb; 49(2): 235–8PubMedCrossRefGoogle Scholar
  391. 391.
    Charvalos E, Tselentis Y, Hamzehpour MM, et al. Evidence for an efflux pump in multidrug-resistant Campylobacterjejuni. Antimicrob Agents Chemother 1995 Sep; 39(9): 2019–22PubMedCrossRefGoogle Scholar
  392. 392.
    Mazzariol A, Tokue Y, Kanegawa TM, et al. High-level fluoroquinolone-resistant clinical isolates of Escherichia colioverproduce multidrug efflux protein AcrA. Antimicrob Agents Chemother 2000 Dec; 44(12): 3441–3PubMedCrossRefGoogle Scholar
  393. 393.
    Wang H, Dzink-Fox JL, Chen M, et al. Genetic characterization of highly fluoroquinolone-resistant clinical Escherichia coli strains from China: role of acrRmutations. Antimicrob Agents Chemother 2001 May; 45(5): 1515–21PubMedCrossRefGoogle Scholar
  394. 394.
    George AM. Multidrug resistance in enteric and other gram-negative bacteria. FEMS Microbiol Lett 1996 May 15; 139(1): 1–10PubMedCrossRefGoogle Scholar
  395. 395.
    Linde HJ, Notka F, Irtenkauf C, et al. Increase in MICs of ciprofloxacin invivoin two closely related clinical isolates of Enterobactercloacae. J Antimicrob Chemother 2002 Apr; 49(4): 625–30PubMedCrossRefGoogle Scholar
  396. 396.
    Deguchi T, Kawamura T, Yasuda M, et al. Invivoselection of Klebsiellapneumoniaestrains with enhanced quinolone resistance during fluoroquinolone treatment of urinary tract infections. Antimicrob Agents Chemother 1997 Jul; 41(7): 1609–11PubMedGoogle Scholar
  397. 397.
    del Mar Tavio M, Vila J, Ruiz J, et al. Decreased permeability and enhanced proton-dependent active efflux in the development of resistance to quinolones in Morganellamorganii. Int J Antimicrob Agents 2000 Mar; 14(2): 157–60PubMedCrossRefGoogle Scholar
  398. 398.
    Ishii H, Sato K, Hoshino K, et al. Active efflux of ofloxacin by a highly quinolone-resistant strain of Proteusvulgaris. J Antimicrob Chemother 1991 Dec; 28(6): 827–36PubMedCrossRefGoogle Scholar
  399. 399.
    Ishida H, Fuziwara H, Kaibori Y, et al. Cloning of multidrug resistance gene pqrAfrom Proteusvulgaris. Antimicrob Agents Chemother 1995 Feb; 39(2): 453–7PubMedCrossRefGoogle Scholar
  400. 400.
    Ghosh AS, Ahamed J, Chauhan KK, et al. Involvement of an efflux system in high-level fluoroquinolone resistance of Shigelladysenteriae. Biochem Biophys Res Commun 1998 Jan 6; 242(1): 54–6PubMedCrossRefGoogle Scholar
  401. 401.
    Perez-Trallero E, Fernandez-Mazarrasa C, Garcia-Rey C, et al. Antimicrobial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039 Streptococcus pyogenesisolates and their ecological relationships: results of a 1-year (1998–1999) multi-center surveillance study in Spain. Antimicrob Agents Chemother 2001 Dec; 45(12): 3334–40PubMedCrossRefGoogle Scholar
  402. 402.
    Levy SB. Active efflux, a common mechanism for biocide and antibiotic resistance. J Appl Microbiol 2002; 92 Suppl.: 65S–71SPubMedCrossRefGoogle Scholar
  403. 403.
    Lambert RJ, Joynson J, Forbes B. The relationships and susceptibilities of some industrial, laboratory and clinical isolates of Pseudomonasaeruginosato some antibiotics and biocides. J Appl Microbiol 2001 Dec; 91(6): 972–84PubMedCrossRefGoogle Scholar
  404. 404.
    Stickler DJ. Susceptibility of antibiotic-resistant Gram-negative bacteria to biocides: a perspective from the study of catheter biofilms. J Appl Microbiol 2002; 92 Suppl.: 163S–70SPubMedCrossRefGoogle Scholar
  405. 405.
    Higgins CS, Murtough SM, Williamson E, et al. Resistance to antibiotics and biocides among non-fermenting Gram-negative bacteria. Clin Microbiol Infect 2001 Jun; 7(6): 308–15PubMedCrossRefGoogle Scholar
  406. 406.
    Nakahara H, Asakawa M, Yonekura I, et al. Benzethonium chloride resistance in Pseudomonasaeruginosaisolated from clinical lesions. Zentralbl Bakteriol Mikrobiol Hyg [A] 1984 Aug; 257(3): 409–13Google Scholar
  407. 407.
    Nakahara H, Kozukue H. Isolation of chlorhexidine-resistant Pseudomonasaeruginosafrom clinical lesions. J Clin Microbiol 1982 Jan; 15(1): 166–8PubMedGoogle Scholar
  408. 408.
    Block C, Furman M. Association between intensity of chlorhexidine use and micro-organisms of reduced susceptibility in a hospital environment. J Hosp Infect 2002 Jul; 51(3): 201–6PubMedCrossRefGoogle Scholar
  409. 409.
    Fraise AP. Biocide abuse and antimicrobial resistance: a cause for concern? J Antimicrob Chemother 2002 Jan; 49(1): 11–2PubMedCrossRefGoogle Scholar
  410. 410.
    Skurray RA, Rouch DA, Lyon BR, et al. Multiresistant Staphylococcusaureus: genetics and evolution of epidemic Australian strains. J Antimicrob Chemother 1988 Apr; 21 Suppl. C: 19–39PubMedCrossRefGoogle Scholar
  411. 411.
    Lyon BR, Skurray R. Antimicrobial resistance of Staphylococcus aureus: genetic basis. Microbiol Rev 1987 Mar; 51(1): 88–134PubMedGoogle Scholar
  412. 412.
    Join-Lambert OF, Michea-Hamzehpour M, Kohler T, et al. Differential selection of multidrug efflux mutants by trovafloxacin and ciprofloxacin in an experimental model of Pseudomonasaeruginosaacute pneumonia in rats. Antimicrob Agents Chemother 2001 Feb; 45(2): 571–6PubMedCrossRefGoogle Scholar
  413. 413.
    Köhler T, Michea-Hamzehpour M, Plesiat P, et al. Differential selection of multidrug efflux systems by quinolones in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1997 Nov; 41(11): 2540–3PubMedGoogle Scholar
  414. 414.
    Hooper DC. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis 2000 Aug; 31 Suppl. 2: S24–8PubMedCrossRefGoogle Scholar
  415. 415.
    Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Infect Dis 2001 Sep 15; 33 Suppl. 3: S147-56Google Scholar
  416. 416.
    Mamber SW, Kolek B, Brookshire KW, et al. Activity of quinolones in the Ames SalmonellaTA102 mutagenicity test and other bacterial genotoxicity assays. Antimicrob Agents Chemother 1993 Feb; 37(2): 213–7PubMedCrossRefGoogle Scholar
  417. 417.
    Ysern P, Clerch B, Castano M, et al. Induction of SOSgenes in Escherichia coliand mutagenesis in Salmonellatyphimurium by fluoroquinolones. Mutagenesis 1990 Jan; 5(1): 63–6PubMedCrossRefGoogle Scholar
  418. 418.
    Le Thomas I, Couetdic G, Clermont O, et al. Invivoselection of a target/efflux double mutant of Pseudomonasaeruginosaby ciprofloxacin therapy. J Antimicrob Chemother 2001 Oct; 48(4): 553–5PubMedCrossRefGoogle Scholar
  419. 419.
    Zhanel GG, Karlowsky JA, Saunders MH, et al. Development of multiple-antibiotic-resistant (Mar) mutants of Pseudomonas aeruginosaafter serial exposure to fluoroquinolones. Antimicrob Agents Chemother 1995 Feb; 39(2): 489–95PubMedCrossRefGoogle Scholar
  420. 420.
    Lomovskaya O, Lee A, Hoshino K, et al. Use of a genetic approach to evaluate the consequences of inhibition of efflux pumps in Pseudomonasaeruginosa. Antimicrob Agents Chemother 1999 Jun; 43(6): 1340–6PubMedGoogle Scholar
  421. 421.
    Lee A, Mao W, Warren MS, et al. Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance. J Bacteriol 2000 Jun; 182(11): 3142–50PubMedCrossRefGoogle Scholar
  422. 422.
    Plesiat P, Nikaido H. Outer membranes of gram-negative bacteria are permeable to steroid probes. Mol Microbiol 1992 May; 6(10): 1323–33PubMedCrossRefGoogle Scholar
  423. 423.
    Vaara M. The outer membrane as the penetration barrier against mupirocin in gram-negative enteric bacteria. J Antimicrob Chemother 1992 Feb; 29(2): 221–2PubMedCrossRefGoogle Scholar
  424. 424.
    Yethon JA, Gunn JS, Ernst RK, et al. Salmonellaenterica serovar typhimurium waaPmutants show increased susceptibility to polymyxin and loss of virulence invivo. Infect Immun 2000 Aug; 68(8): 4485–91PubMedCrossRefGoogle Scholar
  425. 425.
    Yethon JA, Heinrichs DE, Monteiro MA, et al. Involvement of waaY, waaQ, and waaPin the modification of Escherichia coli lipopolysaccharide and their role in the formation of a stable outer membrane. J Biol Chem 1998 Oct 9; 273(41): 26310–6PubMedCrossRefGoogle Scholar
  426. 426.
    Vaara M. Agents that increase the permeability of the outer membrane. Microbiol Rev 1992 Sep; 56(3): 395–411PubMedGoogle Scholar
  427. 427.
    Fralick JA, Burns-Keliher LL. Additive effect of tolCand rfa mutations on the hydrophobic barrier of the outer membrane of Escherichia coliK-12. J Bacteriol 1994 Oct; 176(20): 6404–6PubMedGoogle Scholar
  428. 428.
    Lucas CE, Hagman KE, Levin JC, et al. Importance of lipooligosaccharide structure in determining gonococcal resistance to hydrophobic antimicrobial agents resulting from the mtr efflux system. Mol Microbiol 1995 Jun; 16(5): 1001–9PubMedCrossRefGoogle Scholar
  429. 429.
    Li XZ, Nikaido H, Williams KE. Silver-resistant mutants of Escherichia colidisplay active efflux of Ag+ and are deficient in porins. J Bacteriol 1997 Oct; 179(19): 6127–32PubMedGoogle Scholar
  430. 430.
    Nikaido H, Normark S. Sensitivity of Escherichia colito various β-lactams is determined by the interplay of outer membrane permeability and degradation by periplasmic β-lactamases: a quantitative predictive treatment. Mol Microbiol 1987 Jul; 1(1): 29–36PubMedCrossRefGoogle Scholar
  431. 431.
    Li XZ, Zhang L, Poole K. Interplay between the MexA-MexB-OprM multidrug efflux system and the outer membrane barrier in the multiple antibiotic resistance of Pseudomonasaeruginosa. J Antimicrob Chemother 2000 Apr; 45(4): 433–6PubMedCrossRefGoogle Scholar
  432. 432.
    Plesiat P, Aires JR, Godard C, et al. Use of steroids to monitor alterations in the outer membrane of Pseudomonasaeruginosa. J Bacteriol 1997 Nov; 179(22): 7004–10PubMedGoogle Scholar
  433. 433.
    Germ M, Yoshihara E, Yoneyama H, et al. Interplay between the efflux pump and the outer membrane permeability barrier in fluorescent dye accumulation in Pseudomonasaeruginosa. Biochem Biophys Res Commun 1999 Aug 2; 261(2): 452–5PubMedCrossRefGoogle Scholar
  434. 434.
    Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonasaeruginosa:our worst nightmare? Clin Infect Dis 2002 Mar 1; 34(5): 634–40PubMedCrossRefGoogle Scholar
  435. 435.
    Lakaye B, Dubus A, Lepage S, et al. When drug inactivation renders the target irrelevant to antibiotic resistance: a case story with β-lactams. Mol Microbiol 1999 Jan; 31(1): 89–101PubMedCrossRefGoogle Scholar
  436. 436.
    Nakae T, Nakajima A, Ono T, et al. Resistance to β-lactam antibiotics in Pseudomonasaeruginosadue to interplay between the MexAB-OprM efflux pump and β-lactamase. Antimicrob Agents Chemother 1999 May; 43(5): 1301–3PubMedGoogle Scholar
  437. 437.
    Masuda N, Gotoh N, Ishii C, et al. Interplay between chromosomal β-lactamase and the MexAB-OprM efflux system in intrinsic resistance to β-lactams in Pseudomonasaeruginosa. Antimicrob Agents Chemother 1999 Feb; 43(2): 400–2PubMedGoogle Scholar
  438. 438.
    Srikumar R, Tsang E, Poole K. Contribution of the MexAB-OprM multidrug efflux system to the β-lactam resistance of penicillin-binding protein and β-lactamase-derepressed mutants of Pseudomonasaeruginosa. J Antimicrob Chemother 1999 Oct; 44(4): 537–40PubMedCrossRefGoogle Scholar
  439. 439.
    Li XZ, Zhamg L, McKay GA, et al. Role of the acetyltransferase AAC(6')-Iz modifying enzyme in aminoglycoside resistance in Stenotrophomonasmaltophilia. J Antimicrob Chemother 2003; 51(4): 803–11PubMedCrossRefGoogle Scholar
  440. 440.
    Kaatz GW, Seo SM. Mechanisms of fluoroquinolone resistance in genetically related strains of Staphylococcusaureus. Antimicrob Agents Chemother 1997 Dec; 41(12): 2733–7PubMedGoogle Scholar
  441. 441.
    Nakajima A, Sugimoto Y, Yoneyama H, et al. High-level fluoroquinolone resistance in Pseudomonasaeruginosadue to interplay of the MexAB-OprM efflux pump and the DNA gyrase mutation. Microbiol Immunol 2002; 46(6): 391–5PubMedGoogle Scholar
  442. 442.
    Veal WL, Nicholas RA, Shafer WM. Overexpression of the MtrC-MtrD-MtrE efflux pump due to an mtrRmutation is required for chromosomally mediated penicillin resistance in Neisseriagonorrkoeae. J Bacteriol 2002 Oct; 184(20): 5619–24PubMedCrossRefGoogle Scholar
  443. 443.
    Maiti SN, Phillips OA, Micetich RG, et al. Beta-lactamase inhibitors: agents to overcome bacterial resistance. Curr Med Chem 1998 Dec; 5(6): 441–56PubMedGoogle Scholar
  444. 444.
    Chopra I. New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors. Drug Resist Updat 2002 Aug 6; 5 (3–4): 119CrossRefGoogle Scholar
  445. 445.
    Nelson ML, Levy SB. Reversal of tetracycline resistance mediated by different bacterial tetracycline resistance determinants by an inhibitor of the Tet(B) antiport protein. Antimicrob Agents Chemother 1999 Jul; 43(7): 1719–24PubMedGoogle Scholar
  446. 446.
    Nelson ML, Park BH, Levy SB. Molecular requirements for the inhibition of the tetracycline antiport protein and the effect of potent inhibitors on the growth of tetracycline-resistant bacteria. J Med Chem 1994 Apr 29; 37(9): 1355–61PubMedCrossRefGoogle Scholar
  447. 447.
    Rothstein DM, McGlynn M, Bernan V, et al. Detection of tetracyclines and efflux pump inhibitors. Antimicrob Agents Chemother 1993 Aug; 37(8): 1624–9PubMedCrossRefGoogle Scholar
  448. 448.
    Nelson ML. Modulation of antibiotic efflux in bacteria. Curr Med Chem-Anti-Infective Agents 2002; 1(1): 35–54CrossRefGoogle Scholar
  449. 449.
    Hirata T, Wakatabe R, Nielsen J, et al. A novel compound, 1,1-dimethyl-5 (1-hydroxypropyl)-4,6,7-trimethylindan, is an effective inhibitor of the tet(K@#@)gene-encoded metal-tetracycline/ H+ antiporter of Staphylococcusaureus. FEBS Lett 1997 Jul 28; 412(2): 337–40PubMedCrossRefGoogle Scholar
  450. 450.
    Hirata T, Wakatabe R, Nielsen J, et al. Screening of an inhibitor of the tetracycline efflux pump in a tetracycline-resistant clinical-isolate of Staphylococcusaureus743. Biol Pharm Bull 1998 Jul; 21(7): 678–81PubMedCrossRefGoogle Scholar
  451. 451.
    Barrett JF. MC-207110 Daiichi Seiyaku/Microcide Pharmaceuticals. Curr Opin Investig Drugs 2001 Feb; 2(2): 212–5PubMedGoogle Scholar
  452. 452.
    Ryan BM, Dougherty TJ, Beaulieu D, et al. Efflux in bacteria: what do we really know about it? Expert Opin Investig Drugs 2001 Aug; 10(8): 1409–22PubMedCrossRefGoogle Scholar
  453. 453.
    Lewis K. In search of natural substrates and inhibitors of MDR pumps. J Mol Microbiol Biotechnol 2001 Apr; 3(2): 247–54PubMedGoogle Scholar
  454. 454.
    Wigler PW, Patterson FK. Inhibition of the multidrug resistance efflux pump. Biochim Biophys Acta 1993 Oct 29; 1154(2): 173–81PubMedCrossRefGoogle Scholar
  455. 455.
    Martin SK, Oduola AM, Milhous WK. Reversal of chloroquine resistance in Plasmodiumfalciparumby verapamil. Science 1987 Feb 20; 235(4791): 899–901PubMedCrossRefGoogle Scholar
  456. 456.
    Cohn RC, Rudzienski L, Putnam RW. Verapamil-tobramycin synergy in Pseudomonascepaciabut not Pseudomonas aeruginosainvitro. Chemotherapy 1995 Sep–Oct; 41(5): 330–3PubMedCrossRefGoogle Scholar
  457. 457.
    Brenwald NP, Gill MJ, Wise R. The effect of reserpine, an inhibitor of multi-drug efflux pumps, on the in-vitrosusceptibilities of fluoroquinolone-resistant strains of Streptococcus pneumoniaeto norfloxacin. J Antimicrob Chemother 1997 Sep; 40(3): 458–60PubMedCrossRefGoogle Scholar
  458. 458.
    Gibbons S, Udo EE. The effect of reserpine, a modulator of multidrug efflux pumps, on the invitroactivity of tetracycline against clinical isolates of methicillin resistant Staphylococcus aureus(MRSA) possessing the tet(K@#@)determinant. Phytother Res 2000 Mar; 14(2): 139–40PubMedCrossRefGoogle Scholar
  459. 459.
    Beyer R, Pestova E, Millichap JJ, et al. A convenient assay for estimating the possible involvement of efflux of fluoroquino-lones by Streptococcus pneumoniaeand Staphylococcusaureus: evidence for diminished moxifloxacin, sparfloxacin, and trovafloxacin efflux. Antimicrob Agents Chemother 2000 Mar; 44(3): 798–801PubMedCrossRefGoogle Scholar
  460. 460.
    Markham PN, Westhaus E, Klyachko K, et al. Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus. Antimicrob Agents Chemother 1999 Oct; 43(10): 2404–8PubMedGoogle Scholar
  461. 461.
    Neyfakh AA, Borsch CM, Kaatz GW. Fluoroquinolone resistance protein NorA of Staphylococcusaureusis a multidrug efflux transporter. Antimicrob Agents Chemother 1993 Jan; 37(1): 128–9PubMedCrossRefGoogle Scholar
  462. 462.
    Stermitz FR, Lorenz P, Tawara JN, et al. Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci U S A 2000 Feb 15; 97(4): 1433–7PubMedCrossRefGoogle Scholar
  463. 463.
    Renau TE, Leger R, Flamme EM, et al. Inhibitors of efflux pumps in Pseudomonasaeruginosapotentiate the activity of the fluoroquinolone antibacterial levofloxacin. J Med Chem 1999 Dec 2; 42(24): 4928–31PubMedCrossRefGoogle Scholar
  464. 464.
    Renau TE, Leger R, Flamme EM, et al. Addressing the stability of C-capped dipeptide efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonasaeruginosa. Bioorg Med Chem Lett 2001 Mar 12; 11(5): 663–7PubMedCrossRefGoogle Scholar
  465. 465.
    Lomovskaya O, Warren MS, Lee A, et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonasaeruginosa:novel agents for combination therapy. Antimicrob Agents Chemother 2001 Jan; 45(1): 105–16PubMedCrossRefGoogle Scholar
  466. 466.
    Griffith D, Lomovskaya O, Lee V, et al. Potentiation of levofloxacin by a broad-spectrum efflux inhibitor (EPI) in mouse models of infection caused by Pseudomonasaeruginosa [abstract no. 1268]. Abstracts of the 39th Interscience conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, DC; 1999 Sep 26–29; San Francisco (CA), 327Google Scholar
  467. 467.
    Renau TE, Leger R, Yen R, et al. Peptidomimetics of efflux pump inhibitors potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg Med Chem Lett 2002 Mar 11; 12(5): 763–6PubMedCrossRefGoogle Scholar
  468. 468.
    Lee MD, Galazzo JL, Staley AL, et al. Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco 2001 Jan–Feb; 56(1–2): 81–5PubMedCrossRefGoogle Scholar
  469. 469.
    Fukuda H, Hori S, Hiramatsu K. Antibacterial activity of gatifloxacin (AM-1155, CG5501, BMS-206584), a newly developed fluoroquinolone, against sequentially acquired quinolone-resistant mutants and the norAtransformant of Staphylococcus aureus. Antimicrob Agents Chemother 1998 Aug; 42(8): 1917–22PubMedGoogle Scholar
  470. 470.
    Gootz TD, Zaniewski RP, Haskell SL, et al. Activities of trovafloxacin compared with those of other fluoroquinolones against purified topoisomerases and gyrAand grlAmutants of Staphylococcusaureus. Antimicrob Agents Chemother 1999 Aug; 43(8): 1845–55PubMedGoogle Scholar
  471. 471.
    Ince D, Hooper DC. Mechanisms and frequency of resistance to premafloxacin in Staphylococcusaureus: novel mutations suggest novel drug-target interactions. Antimicrob Agents Chemother 2000 Dec; 44(12): 3344–50PubMedCrossRefGoogle Scholar
  472. 472.
    Zhong P, Shortridge VD. The role of efflux in macrolide resistance. Drug Resist Updat 2000 Dec; 3(6): 325–9PubMedCrossRefGoogle Scholar
  473. 473.
    Chu DT. Recent progress in novel macrolides, quinolones, and 2-pyridones to overcome bacterial resistance. Med Res Rev 1999 Nov; 19(6): 497–520PubMedCrossRefGoogle Scholar
  474. 474.
    Brennan L, Duignan J, Petitpas J, et al. CP-544372: MIC90 studies and killing kinetics against key respiratory tract pathogens [abstract no. F-124]. Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, DC; 1998 Sep 24–27; San Diego (CA), 264Google Scholar
  475. 475.
    Someya Y, Yamaguchi A, Sawai T. A novel glycylcycline, 9-(N,N-dimethylglycylamido)-6-demethyl-6-deoxytetracycline, is neither transported nor recognized by the transposon Tn10-encoded metal-tetracycline/H+ antiporter. Antimicrob Agents Chemother 1995 Jan; 39(1): 247–9PubMedCrossRefGoogle Scholar
  476. 476.
    Benveniste R, Davies J. Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc Natl Acad Sci U S A 1973 Aug; 70(8): 2276–80PubMedCrossRefGoogle Scholar
  477. 477.
    Davies J. Inactivation of antibiotics and the dissemination of resistance genes. Science 1994 Apr 15; 264(5157): 375–82PubMedCrossRefGoogle Scholar
  478. 478.
    Davies J. Another look at antibiotic resistance: 1991 Fred Griffith Review Lecture. J Gen Microbiol 1992 Aug; 138 (Pt 8): 1553–9PubMedCrossRefGoogle Scholar
  479. 479.
    Marshall CG, Lessard IA, Park I, et al. Glycopeptide antibiotic resistance genes in glycopeptide-producing organisms. Antimicrob Agents Chemother 1998 Sep; 42(9): 2215–20PubMedGoogle Scholar
  480. 480.
    Krulwich TA, Jin J, Guffanti AA, et al. Functions of tetracycline efflux proteins that do not involve tetracycline. J Mol Microbiol Biotechnol 2001 Apr; 3(2): 237–46PubMedGoogle Scholar
  481. 481.
    Wang W, Guffanti AA, Wei Y, et al. Two types of Bacillus subtilisTetA(L @#@)deletion strains reveal the physiological importance of TetA(L @#@)in K+ acquisition as well as in Na+, alkali, and tetracycline resistance. J Bacteriol 2000 Apr; 182(8): 2088–95PubMedCrossRefGoogle Scholar

Copyright information

© adis data information BV 2004

Authors and Affiliations

  1. 1.Department of Molecular and Cell BiologyUniversity of CaliforniaBerkeleyUSA

Personalised recommendations