1887

Chapter 19 : Role, Structure, and Function of Multidrug Efflux Pumps in Gram-Negative Bacteria

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in
Zoomout

Role, Structure, and Function of Multidrug Efflux Pumps in Gram-Negative Bacteria, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817572/9781555813291_Chap19-1.gif /docserver/preview/fulltext/10.1128/9781555817572/9781555813291_Chap19-2.gif

Abstract:

Genomes of gram-negative bacteria usually contain multiple copies of genes belonging to each of the families of multidrug transporters, such as SMR (small multidrug resistance), MFS (major facilitator superfamily), MATE (multidrug and toxic compound extrusion), and RND (resistance nodulation division). Due to the predominant role RND pumps play in the resistance (both intrinsic and acquired) to commonly used antibiotics, this chapter discusses the pumps of this type in detail; however, the discussion is limited to and , as representative organisms. For soil and water dwellers, it is difficult to pinpoint the “natural” substrate for their main efflux pumps. However, gram-negative bacteria have always faced toxic chemicals in the environment, and outer membrane (OM) cannot completely shut out lipophilic compounds, which can diffuse, albeit slowly, across the asymmetric bilayer of OM. Living in a natural habitat surrounded by high concentrations of bile salts and other antimicrobial inhibitors such as fatty acids, cells are armed with the OM as well as a wide range of efflux pumps. In , , which is divergently transcribed from the genes, encodes a repressor. Perhaps because the inactivation of AcrR results in a too high level of production of AcrAB, it seems to serve only a subsidiary role in the regulation of AcrAB expression.

Citation: Nikaido H. 2005. Role, Structure, and Function of Multidrug Efflux Pumps in Gram-Negative Bacteria, p 261-274. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch19

Key Concept Ranking

Major Facilitator Superfamily
0.5234375
Integral Membrane Proteins
0.41109717
0.5234375
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of Figure 1
Figure 1

RND pump complex is likely to capture its amphiphilic substrates from the outer leaflet of IM.

Citation: Nikaido H. 2005. Role, Structure, and Function of Multidrug Efflux Pumps in Gram-Negative Bacteria, p 261-274. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch19
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Three-dimensional structure of the AcrB trimer with liganded ciprofloxacin molecules. This structure shows the N109A mutant AcrB trimer, with six molecules of bound ciprofloxacin (Yu, McDermott, and Nikaido, submitted for publication). The three protomers of AcrB are shown as ribbon diagrams in different shades of gray. The ciprofloxacin molecules are shown in ball-and-stick models, those in the central cavity in light gray, and those in the periplasmic site in black. The drawing was made with DS Viewer Pro (Accelrys, San Diego, Calif.).

Citation: Nikaido H. 2005. Role, Structure, and Function of Multidrug Efflux Pumps in Gram-Negative Bacteria, p 261-274. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch19
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

Hypothetical pathway for the lateral capture of substrates by RND group transporters. Cationic dyes and aminoglycosides become adsorbed at the interface region and on the surface of the outer leaflet of IM. Ciprofloxacin is partitioned into IM, with the protonated piperazine amino group near the interface. These substrates diffuse laterally through vestibules into the central cavity, where they become bound to its wall.

Citation: Nikaido H. 2005. Role, Structure, and Function of Multidrug Efflux Pumps in Gram-Negative Bacteria, p 261-274. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch19
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817572.chap19
1. Adewoye, L.,, A. Sutherland,, R. Srikumar,, and K. Poole. 2002. The mexR repressor of the mexAB-oprM multidrug efflux operon in Pseudomonas aeruginosa: characterization of mutations compromising activity. J. Bacteriol. 184: 4308 4312.
2. Aendekerk, S.,, B. Ghysels,, P. Cornelis,, and C. Baysse. 2002. Characterization of a new efflux pump, MexGHI-OpmD, from Pseudomonas aeruginosa that confers resistance to vanadium. Microbiology 148: 2371 2381.
3. Aires, J. R.,, T. Kohler,, H. Nikaido,, and P. Plesiat. 1999. Involvement of an active efflux system in the natural resistance of Pseudomonas aeruginosa to aminoglycosides. Antimicrob. Agents Chemother. 43: 2624 2628.
3a. Aires, J. R.,, and H. Nikaido. 2005. Aminoglycosides are captured from both periplasm and cytoplasm by the AcrD multidrug efflux transporter of Escherichia coli. J. Bacteriol. 187: 1923 1929.
4. Akama, H.,, T. Matsuura,, S. Kashiwagi,, H. Yoneyama,, S. Narita,, T. Tsukihara,, A. Nakagawa,, and T. Nakae. 2004. Crystal structure of the membrane fusion protein, MexA, of the multidrug transporter in Pseudomonas aeruginosa. J. Biol. Chem. 279: 25939 25942.
5. Alekshun, M. N.,, S. B. Levy,, T. R. Mealy,, B. A. Seaton,, and J. F. Head. 2001. The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 Å resolution. Nat. Struct. Biol. 8: 710 714.
6. Ariza, R. R.,, Z. Li,, N. Ringstad,, and B. Demple. 1995. Activation of multiple antibiotic resistance and binding of stressinducible promoters by Escherichia coli Rob protein. J. Bacteriol. 177: 1655 1661.
7. Avila-Sakar, A. J.,, S. Misaghi,, E. M. Wilson-Kubalek,, K. H. Downing,, H. Zgurskaya,, H. Nikaido,, and E. Nogales. 2001. Lipid-layer crystallization and preliminary three-dimensional structural analysis of AcrA, the periplasmic component of a bacterial multidrug efflux pump. J. Struct. Biol. 136: 81 88.
8. Baranova, N.,, and H. Nikaido. 2002. The baeSR twocomponent regulatory system activates transcription of the yegMNOB (mdtABCD) transporter gene cluster in Escherichia coli and increases its resistance to novobiocin and deoxycholate. J. Bacteriol. 184: 4168 4176.
9. Chuanchuen, R.,, K. Beinlich,, T. T. Hoang,, A. Becher,, R. R. Karkhoff-Schweizer,, and H. P. Schweizer. 2001. Crossresistance 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. 45: 428 432.
10. Chuanchuen, R.,, C. T. Narasaki,, and H. P. Schweizer. 2002. The MexJK efflux pump of Pseudomonas aeruginosa requires OprM for antibiotic efflux but not for efflux of triclosan. J. Bacteriol. 184: 5036 5044.
11. Chung, Y. J.,, and M. H. Saier, Jr. 2002. Overexpression of the Escherichia coli sugE gene confers resistance to a narrow range of quaternary ammonium compounds. J. Bacteriol. 184: 2543 2545.
12. Cohen, S. P.,, H. Hachler,, and S. B. Levy. 1993. Genetic and functional analysis of the multiple antibiotic resistance ( mar) locus in Escherichia coli. J. Bacteriol. 175: 1484 1492.
13. Dröge, M.,, A. Pühler,, and W. Selbitschka. 2000. Phenotypic and molecular characterization of conjugative antibiotic resistance plasmids isolated from bacterial communities of activated sludge. Mol. Gen. Genet. 263: 471 482.
14. Elkins, C. A.,, and H. Nikaido. 2003. Chimeric analysis of AcrA function reveals the importance of its C-terminal domain in its interaction with the AcrB multidrug efflux pump. J. Bacteriol. 185: 5349 5356.
15. Elkins, C. A.,, and H. Nikaido. 2002. 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. 184: 6490 6498.
16. Fralick, J. A. 1996. Evidence that TolC is required for functioning of the Mar/AcrAB efflux pump of Escherichia coli. J. Bacteriol. 178: 5803 5805.
17. Furukawa, H.,, J. T. Tsay,, S. Jackowski,, Y. Takamura,, and C. O. Rock. 1993. Thiolactomycin resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB. J. Bacteriol. 175: 3723 3729.
18. Gotoh, N.,, H. Tsujimoto,, M. Tsuda,, K. Okamoto,, A. Nomura,, T. Wada,, M. Nakahashi,, and T. Nishino. 1998. Characterization of the MexC-MexD-OprJ multidrug efflux system in δmexA-mexB-oprM mutants of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 42: 1938 1943.
19. Grkovic, S.,, M. H. Brown,, and R. A. Skurray. 2002. Regulation of bacterial drug export systems. Microbiol. Mol. Biol. Rev. 66: 671 701.
20. Helling, R. B.,, B. K. Janes,, H. Kimball,, T. Tran,, M. Bundesmann,, P. Check,, D. Phelan,, and C. Miller. 2002. Toxic waste disposal in Escherichia coli. J. Bacteriol. 184: 3699 3703.
21. Hidalgo, E.,, H. Ding,, and B. Demple. 1997. Redox signal transduction via iron-sulfur clusters in the SoxR transcription activator. Trends Biochem. Sci. 22: 207 210.
22. Ip, H.,, K. Stratton,, H. Zgurskaya,, and J. Liu. 2003. pH-induced conformational changes of AcrA, the membrane fusion protein of Escherichia coli multidrug efflux system. J. Biol. Chem. 278: 50474 50482.
23. Köhler, T.,, S. F. Epp,, L. K. Curty,, and J. C. Pechère. 1999. Characterization of MexT, the regulator of the MexE-MexFOprN multidrug efflux system of Pseudomonas aeruginosa. J. Bacteriol. 181: 6300 6305.
24. Köhler, T.,, M. Michea-Hamzehpour,, U. Henze,, N. Gotoh,, L. K. Curty,, and J. C. Pechère. 1997. Characterization of MexE-MexF-OprN, a positively regulated multidrug efflux system of Pseudomonas aeruginosa. Mol. Microbiol. 23: 345 354.
25. Koronakis, V.,, A. Sharff,, E. Koronakis,, B. Luisi,, and C. Hughes. 2000. Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature 405: 914 919.
26. Koteiche, H. A.,, M. D. Reeves,, and H. S. McHaourab. 2003. Structure of the substrate binding pocket of the multidrug transporter EmrE: site-directed spin labeling of transmembrane segment 1. Biochemistry 42: 6099 6105.
27. Li, H.,, and J. T. Park. 1999. The periplasmic murein peptidebinding protein MppA is a negative regulator of multiple antibiotic resistance in Escherichia coli. J. Bacteriol. 181: 4842 4847.
28. Li, X. Z.,, N. Barre,, and K. Poole. 2000. 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 46: 885 893.
29. Li, X. Z.,, D. M. Livermore,, and H. Nikaido. 1994. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob. Agents Chemother. 38: 1732 1741.
30. Li, X. Z.,, D. Ma,, D. M. Livermore,, and H. Nikaido. 1994. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to betalactam resistance. Antimicrob. Agents Chemother. 38: 1742 1752.
31. Li, X. Z.,, and H. Nikaido. 2004. Efflux-mediated drug resistance in bacteria. Drugs 64: 159 204.
32. Li, X. Z.,, H. Nikaido,, and K. Poole. 1995. Role of mexAmexB- oprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 39: 1948 1953.
33. Li, X.-Z.,, K. Poole,, and H. Nikaido. 2003. Contributions of MexAB-OprM and an EmrE homolog to intrinsic resistance of Pseudomonas aeruginosa to aminoglycosides and dyes. Antimicrob. Agents Chemother. 47: 27 33.
34. Lomovskaya, O.,, and K. Lewis. 1992. Emr, an Escherichia coli locus for multidrug resistance. Proc. Natl. Acad. Sci. USA 89: 8938 8942.
35. Ma, D.,, M. Alberti,, C. Lynch,, H. Nikaido,, and J. E. Hearst. 1996. The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals. Mol. Microbiol. 19: 101 112.
36. Ma, D.,, D. N. Cook,, M. Alberti,, N. G. Pon,, H. Nikaido,, and J. E. Hearst. 1995. Genes acrA and acrB encode a stressinduced efflux system of Escherichia coli. Mol. Microbiol. 16: 45 55.
37. Ma, D.,, D. N. Cook,, M. Alberti,, N. G. Pon,, H. Nikaido,, and J. E. Hearst. 1993. Molecular cloning and characterization of acrA and acrE genes of Escherichia coli. J. Bacteriol. 175: 6299 6313.
38. Ma, D.,, D. N. Cook,, J. E. Hearst,, and H. Nikaido. 1994. Efflux pumps and drug resistance in gram-negative bacteria. Trends Microbiol. 2: 489 493.
39. Mao, W.,, M. S. Warren,, D. S. Black,, T. Satou,, T. Murata,, T. Nishino,, N. Gotoh,, and O. Lomovskaya. 2002. On the mechanism of substrate specificity by resistance nodulation division (RND)-type multidrug resistance pumps: the large periplasmic loops of MexD from Pseudomonas aeruginosa are involved in substrate recognition. Mol. Microbiol. 46: 889 901.
40. Martin, R. G.,, and J. L. Rosner. 1995. Binding of purified multiple antibiotic-resistance repressor protein (MarR) to mar operator sequences. Proc. Natl. Acad. Sci. USA 92: 5456 5460.
41. Masuda, N.,, N. Gotoh,, S. Ohya,, and T. Nishino. 1996. Quantitative correlation between susceptibility and OprJ production in NfxB mutants of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 40: 909 913.
42. Masuda, N.,, and S. Ohya. 1992. Cross-resistance to meropenem, cephems, and quinolones in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 36: 1847 1851.
43. Masuda, N.,, E. Sakagawa,, and S. Ohya. 1995. Outer membrane proteins responsible for multiple drug resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 39: 645 649.
44. Masuda, N.,, E. Sakagawa,, S. Ohya,, N. Gotoh,, and T. Nishino. 2001. Hypersusceptibility of the Pseudomonas aeruginosa nfxB mutant to β-lactams due to reduced expression of the ampC β- lactamase. Antimicrob. Agents Chemother. 45: 1284 1286.
45. Masuda, N.,, E. Sakagawa,, S. Ohya,, N. Gotoh,, H. Tsujimoto,, and T. Nishino. 2000. Contribution of the MexX-MexYoprM efflux system to intrinsic resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44: 2242 2246.
46. Masuda, N.,, E. Sakagawa,, S. Ohya,, N. Gotoh,, H. Tsujimoto,, and T. Nishino. 2000. Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-OprM efflux pumps in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44: 3322 3327.
47. Mazzariol, A.,, G. Cornaglia,, and H. Nikaido. 2000. Contributions of the AmpC beta-lactamase and the AcrAB multidrug efflux system in intrinsic resistance of Escherichia coli K-12 to beta-lactams. Antimicrob. Agents Chemother. 44: 1387 1390.
48. McMurry, L. M.,, D. A. Aronson,, and S. B. Levy. 1983. Susceptible Escherichia coli cells can actively excrete tetracyclines. Antimicrob. Agents Chemother. 24: 544 551.
49. McMurry, L. M.,, J. C. Cullinane,, and S. B. Levy. 1982. Transport of the lipophilic analog minocycline differs from that of tetracycline in susceptible and resistant Escherichia coli strains. Antimicrob. Agents Chemother. 22: 791 799.
50. McMurry, L. M.,, M. Oethinger,, and S. B. Levy. 1998. Overexpression of marA, soxS, or acrAB produces resistance to triclosan in laboratory and clinical strains of Escherichia coli. FEMS Microbiol. Lett. 166: 305 309.
51. Mine, T.,, Y. Morita,, A. Kataoka,, T. Mizushima,, and T. Tsuchiya. 1998. Evidence for chloramphenicol/H+ antiport in Cmr (MdfA) system of Escherichia coli and properties of the antiporter. J. Biochem. (Tokyo) 124: 187 193.
52. Mine, T.,, Y. Morita,, A. Kataoka,, T. Mizushima,, and T. Tsuchiya. 1999. Expression in Escherichia coli of a new multidrug efflux pump, MexXY, from Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 43: 415 417.
53. Morita, Y.,, Y. Komori,, T. Mima,, T. Kuroda,, T. Mizushima,, and T. Tsuchiya. 2001. 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. 202: 139 143.
54. Murakami, S.,, R. Nakashima,, E. Yamashita,, and A. Yamaguchi. 2002. Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419: 587 593.
55. Muth, T. R.,, and S. Schuldiner. 2000. A membrane-embedded glutamate is required for ligand binding to the multidrug transporter EmrE. EMBO J. 19: 234 240.
56. Nagakubo, S.,, K. Nishino,, T. Hirata,, and A. Yamaguchi. 2002. The putative response regulator BaeR stimulates multidrug resistance of Escherichia coli via a novel multidrug exporter system, MdtABC. J. Bacteriol. 184: 4161 4167.
57. Nakajima, H.,, K. Kobayashi,, M. Kobayashi,, H. Asako,, and R. Aono. 1995. Overexpression of the robA gene increases organic solvent tolerance and multiple antibiotic and heavy metal ion resistance in Escherichia coli. Appl. Environ. Microbiol. 61: 2302 2307.
58. Nakayama, K.,, Y. Ishida,, M. Ohtsuka,, H. Kawato,, K. Yoshida,, Y. Yokomizo,, S. Hosono,, T. Ohta,, K. Hoshino,, H. Ishida,, T. E. Renau,, R. Leger,, J. Z. Zhang,, V. J. Lee,, and W. J. Watkins. 2003. MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: Discovery and early strategies for lead optimization. Bioorg. Med. Chem. Lett. 13: 4201 4204.
59. Nehme, D.,, X. Z. Li,, R. Elliot,, and K. Poole. 2004. Assembly of the MexAB-OprM multidrug efflux system of Pseudomonas aeruginosa: identification and characterization of mutations in mexA compromising MexA multimerization and interaction with MexB. J. Bacteriol. 186: 2973 2983.
60. Nikaido, H. 1996. Multidrug efflux pumps of gram-negative bacteria. J. Bacteriol. 178: 5853 5859.
61. Nikaido, H. 1989. Outer membrane barrier as a mechanism of antimicrobial resistance. Antimicrob. Agents Chemother. 33: 1831 1836.
62. Nikaido, H. 2001. Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin. Cell Dev. Biol. 12: 215 223.
63. Nikaido, H. 1994. Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264: 382 388.
64. Nikaido, H. 1998. The role of outer membrane and efflux pumps in the resistance of gram-negative bacteria. Can we improve drug access? Drug Res. Updates 1: 93 98.
65. Nikaido, H.,, M. Basina,, V. Nguyen,, and E. Y. Rosenberg. 1998. Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those β-lactam antibiotics containing lipophilic side chains. J. Bacteriol. 180: 4686 4692.
66. Nilsen, I. W.,, I. Bakke,, A. Vader,, O. Olsvik,, and M. R. El- Gewely. 1996. Isolation of cmr, a novel Escherichia coli chloramphenicol resistance gene encoding a putative efflux pump. J. Bacteriol. 178: 3188 3193.
67. Nishino, K.,, and A. Yamaguchi. 2001. Analysis of a complete library of putative drug transporter genes in Escherichia coli. J. Bacteriol. 183: 5803 5812.
68. Nishino, K.,, and A. Yamaguchi. 2002. EvgA of the twocomponent signal transduction system modulates production of the yhiUV multidrug transporter in Escherichia coli. J. Bacteriol. 184: 2319 2323.
69. Ochs, M. M.,, M. P. McCusker,, M. Bains,, and R. E. Hancock. 1999. Negative regulation of the Pseudomonas aeruginosa outer membrane porin OprD selective for imipenem and basic amino acids. Antimicrob. Agents Chemother. 43: 1085 1090.
70. Okamoto, K.,, N. Gotoh,, and T. Nishino. 2002. Extrusion of penem antibiotics by multicomponent efflux systems MexABOprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 46: 2696 2699.
71. Okamoto, K.,, N. Gotoh,, and T. Nishino. 2001. Pseudomonas aeruginosa reveals high intrinsic resistance to penem antibiotics: penem resistance mechanisms and their interplay. Antimicrob. Agents Chemother. 45: 1964 1971.
72. Okusu, H.,, D. Ma,, and H. Nikaido. 1996. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. J. Bacteriol. 178: 306 308.
73. Plésiat, P.,, and H. Nikaido. 1992. Outer membranes of gramnegative bacteria are permeable to steroid probes. Mol. Microbiol. 6: 1323 1333.
74. Poole, K.,, N. Gotoh,, H. Tsujimoto,, Q. Zhao,, A. Wada,, T. Yamasaki,, S. Neshat,, J. Yamagishi,, X. Z. Li,, and T. Nishino. 1996. Overexpression of the mexC-mexD-oprJ efflux operon in nfxB-type multidrug-resistant strains of Pseudomonas aeruginosa. Mol. Microbiol. 21: 713 724.
75. Poole, K.,, K. Krebes,, C. McNally,, and S. Neshat. 1993. Multiple antibiotic resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux operon. J. Bacteriol. 175: 7363 7372.
76. Rahmati, S.,, S. Yang,, A. L. Davidson,, and E. L. Zechiedrich. 2002. Control of the AcrAB multidrug efflux pump by quorum- sensing regulator SdiA. Mol. Microbiol. 43: 677 685.
77. Renau, T. E.,, R. Leger,, L. Filonova,, E. M. Flamme,, M. Wang,, R. Yen,, D. Madsen,, D. Griffith,, S. Chamberland,, M. N. Dudley,, V. J. Lee,, O. Lomovskaya,, W. J. Watkins,, T. Ohta,, K. Nakayama,, and Y. Ishida. 2003. Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett. 13: 2755 2758.
78. Renau, T. E.,, R. Leger,, E. M. Flamme,, J. Sangalang,, M. W. She,, R. Yen,, C. L. Gannon,, D. Griffith,, S. Chamberland,, O. Lomovskaya,, S. J. Hecker,, V. J. Lee,, T. Ohta,, and K. Nakayama. 1999. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J. Med. Chem. 42: 4928 4931.
79. Renau, T. E.,, R. Leger,, R. Yen,, M. W. She,, E. M. Flamme,, J. Sangalang,, C. L. Gannon,, S. Chamberland,, O. Lomovskaya,, and V. J. Lee. 2002. Peptidomimetics of efflux pump inhibitors potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett. 12: 763 766.
80. Rosenberg, E. Y.,, D. Bertenthal,, M. L. Nilles,, K. P. Bertrand,, and H. Nikaido. 2003. Bile salts and fatty acids induce the expression of Escherichia coli AcrAB multidrug efflux pump through their interaction with Rob regulatory protein. Mol. Microbiol. 48: 1609 1619.
81. Rosenberg, E. Y.,, D. Ma,, and H. Nikaido. 2000. AcrD of Escherichia coli is an aminoglycoside efflux pump. J. Bacteriol. 182: 1754 1756.
82. Rosner, J. L.,, B. Dangi,, A. M. Gronenborn,, and R. G. Martin. 2002. Posttranscriptional activation of the transcriptional activator Rob by dipyridyl in Escherichia coli. J. Bacteriol. 184: 1407 1416.
83. Rotem, D.,, N. Sal-man,, and S. Schuldiner. 2001. In vitro monomer swapping in EmrE, a multidrug transporter from Escherichia coli, reveals that the oligomer is the functional unit. J. Biol. Chem. 276: 48243 48249.
84. Schuldiner, S.,, D. Granot,, S. S. Mordoch,, S. Ninio,, D. Rotem,, M. Soskin,, C. G. Tate,, and H. Yerushalmi. 2001. Small is mighty: EmrE, a multidrug transporter as an experimental paradigm. News Physiol. Sci. 16: 130 134.
85. Shinabarger, D. L.,, K. R. Marotti,, R. W. Murray,, A. H. Lin,, E. P. Melchior,, S. M. Swaney,, D. S. Dunyak,, W. F. Demyan,, and J. M. Buysse. 1997. Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob. Agents Chemother. 41: 2132 2136.
86. Soskine, M.,, Y. Adam,, and S. Schuldiner. 2004. Direct evidence for substrate-induced proton release in detergent-solubilized EmrE, a multidrug transporter. J. Biol. Chem. 279: 9951 9955.
87. Soskine, M.,, S. Steiner-Mordoch,, and S. Schuldiner. 2002. Crosslinking of membrane-embedded cysteines reveals contact points in the EmrE oligomer. Proc. Natl. Acad. Sci. USA 99: 12043 12048.
88. Srikumar, R.,, X. Z. Li,, and K. Poole. 1997. Inner membrane efflux components are responsible for β-lactam specificity of multidrug efflux pumps in Pseudomonas aeruginosa. J. Bacteriol. 179: 7875 7881.
89. Srikumar, R.,, C. J. Paul,, and K. Poole. 2000. Influence of mutations in the mexR repressor gene on expression of the MexAMexB- oprM multidrug efflux system of Pseudomonas aeruginosa. J. Bacteriol. 182: 1410 1414.
90. Stover, C. K.,, X. Q. Pham,, A. L. Erwin,, S. D. Mizoguchi,, P. Warrener,, M. J. Hickey,, F. S. Brinkman,, W. O. Hufnagle,, D. J. Kowalik,, M. Lagrou,, R. L. Garber,, L. Goltry,, E. Tolentino,, S. Westbrock-Wadman,, Y. Yuan,, L. L. Brody,, S. N. Coulter,, K. R. Folger,, A. Kas,, K. Larbig,, R. Lim,, K. Smith,, D. Spencer,, G. K. Wong,, Z. Wu,, I. T. Paulsen,, J. Reizer,, M. H. Saier,, R. E. Hancock,, S. Lory,, and M. V. Olson. 2000. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 406: 959 964.
91. Sulavik, M. C.,, C. Houseweart,, C. Cramer,, N. Jiwani,, N. Murgolo,, J. Greene,, B. DiDomenico,, K. J. Shaw,, G. H. Miller,, R. Hare,, and G. Shimer. 2001. Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes. Antimicrob. Agents Chemother. 45: 1126 1136.
92. Tate, C. G.,, E. R. Kunji,, M. Lebendiker,, and S. Schuldiner. 2001. The projection structure of EmrE, a proton-linked multidrug transporter from Escherichia coli, at 7 Å resolution. EMBO J. 20: 77 81.
93. Tate, C. G.,, I. Ubarretxena-Belandia,, and J. M. Baldwin. 2003. Conformational changes in the multidrug transporter EmrE associated with substrate binding. J. Mol. Biol. 332: 229 242.
94. Tauch, A.,, A. Schluter,, N. Bischoff,, A. Goesmann,, F. Meyer,, and A. Puhler. 2003. The 79,370-bp conjugative plasmid pB4 consists of an IncP-1beta backbone loaded with a chromate resistance transposon, the strA-strB streptomycin resistance gene pair, the oxacillinase gene bla (NPS-1), and a tripartite antibiotic efflux system of the resistance-nodulation-division family. Mol. Gen. Genom. 268: 570 84.
95. Thanassi, D. G.,, G. S. Suh,, and H. Nikaido. 1995. Role of outer membrane barrier in efflux-mediated tetracycline resistance of Escherichia coli. J. Bacteriol. 177: 998 1007.
96. Trias, J.,, and H. Nikaido. 1990. Outer membrane protein D2 catalyzes facilitated diffusion of carbapenems and penems through the outer membrane of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 34: 52 57.
97. Tseng, T. T.,, K. S. Gratwick,, J. Kollman,, D. Park,, D. H. Nies,, A. Goffeau,, and M. H. Saier, Jr. 1999. The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J. Mol. Microbiol. Biotechnol. 1: 107 125.
98. Ubarretxena-Belandia, I.,, J. M. Baldwin,, S. Schuldiner,, and C. G. Tate. 2003. Three-dimensional structure of the bacterial multidrug transporter EmrE shows it is an asymmetric homodimer. EMBO J. 22: 6175 6181.
99. Vaara, M. 1993. Antibiotic-supersusceptible mutants of Escherichia coli and Salmonella typhimurium. Antimicrob. Agents Chemother. 37: 2255 2260.
100. Vogne, C.,, J. R. Aires,, C. Bailly,, D. Hocquet,, and P. Plesiat. 2004. Role of the multidrug efflux system MexXY in the emergence of moderate resistance to aminoglycosides among Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob. Agents Chemother. 48: 1676 1680.
101. Wang, H.,, J. L. Dzink-Fox,, M. Chen,, and S. B. Levy. 2001. Genetic characterization of highly fluoroquinolone-resistant clinical Escherichia coli strains from China: role of acrR mutations. Antimicrob. Agents Chemother. 45: 1515 1521.
102. Watkins, W. J.,, Y. Landaverry,, R. Leger,, R. Litman,, T. E. Renau,, N. Williams,, R. Yen,, J. Z. Zhang,, S. Chamberland,, D. Madsen,, D. Griffith,, V. Tembe,, K. Huie,, and M. N. Dudley. 2003. The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors. Bioorg. Med. Chem. Lett. 13: 4241 4244.
103. Webber, M.,, and L. J. Piddock. 2001. Quinolone resistance in Escherichia coli. Vet. Res. 32: 275 284.
104. Westbrock-Wadman, S.,, D. R. Sherman,, M. J. Hickey,, S. N. Coulter,, Y. Q. Zhu,, P. Warrener,, L. Y. Nguyen,, R. M. Shawar,, K. R. Folger,, and C. K. Stover. 1999. Characterization of a Pseudomonas aeruginosa efflux pump contributing to aminoglycoside impermeability. Antimicrob. Agents Chemother. 43: 2975 2983.
105. Williams, R. J.,, D. M. Livermore,, M. A. Lindridge,, A. A. Said,, and J. D. Williams. 1984. Mechanisms of beta-lactam resistance in British isolates of Pseudomonas aeruginosa. J. Med. Microbiol. 17: 283 293.
106. Yerushalmi, H.,, M. Lebendiker,, and S. Schuldiner. 1996. Negative dominance studies demonstrate the oligomeric structure of EmrE, a multidrug antiporter from Escherichia coli. J. Biol. Chem. 271: 31044 31048.
107. Yerushalmi, H.,, S. S. Mordoch,, and S. Schuldiner. 2001. A single carboxyl mutant of the multidrug transporter EmrE is fully functional. J. Biol. Chem. 276: 12744 12748.
108. Yerushalmi, H.,, and S. Schuldiner. 2000. A model for coupling of H(+) and substrate fluxes based on “time-sharing” of a common binding site. Biochemistry 39: 14711 14719.
109. Yu, E. W.,, J. R. Aires,, and H. Nikaido. 2003. AcrB multidrug efflux pump of Escherichia coli: composite substrate-binding cavity of exceptional flexibility generates its extremely wide substrate specificity. J. Bacteriol. 185: 5657 5664.
110. Yu, E. W.,, G. McDermott,, H. I. Zgurskaya,, H. Nikaido,, and D. E. Koshland, Jr. 2003. Structural basis of multiple drugbinding capacity of the AcrB multidrug efflux pump. Science 300: 976 980.
111. Zgurskaya, H. I.,, and H. Nikaido. 1999. AcrA is a highly asymmetric protein capable of spanning the periplasm. J. Mol. Biol. 285: 409 420.
112. Zgurskaya, H. I.,, and H. Nikaido. 1999. Bypassing the periplasm: reconstitution of the AcrAB multidrug efflux pump of Escherichia coli. Proc. Natl. Acad. Sci. USA 96: 7190 7195.
113. Zgurskaya, H. I.,, and H. Nikaido. 2000. Cross-linked complex between oligomeric periplasmic lipoprotein AcrA and the inner-membrane-associated multidrug efflux pump AcrB from Escherichia coli. J. Bacteriol. 182: 4264 4267.
114. Ziha-Zarifi, I.,, C. Llanes,, T. Kohler,, J. C. Pechere,, and P. Plesiat. 1999. In vivo emergence of multidrug-resistant mutants of Pseudomonas aeruginosa overexpressing the active efflux system MexA-MexB-OprM. Antimicrob. Agents Chemother. 43: 287 291.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error