Multidrug efflux pumps: Structure, mechanism, and inhibition

Bacterial Resistance to Antimicrobials, Second Edition

Volumn , Issue , 2007, Pages 45-69

  Lomovskaya, Olga ^a   Zgurskaya, Helen I ^b   Bostian, Keith A ^a   Lewis, Kim ^c  

^a Mpex Pharmaceuticals Inc   (United States)

^b UNIVERSITY OF OKLAHOMA   (United States)

^c NORTHEASTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84856257788     PISSN: None     EISSN: None     Source Type: Book    
DOI: None     Document Type: Chapter

References (147)

1. Saier, M. H., Jr. and I. T. Paulsen. 2001. Phylogeny of multidrug transporters. Semin Cell Dev Biol 12:205-13.
2. Sanchez, L., W. Pan, M. Vinas, and H. Nikaido. 1997. The acrAB homolog of Haemophilus influenzae codes for a functional multidrug efflux pump. J Bacteriol 179:6855-7.
3. Sen, K., J. Hellman, and H. Nikaido. 1988. Porin channels in intact cells of Escherichia coli are not affected by Donnan potentials across the outer membrane. J Biol Chem 263:1182-7.
4. Lomovskaya, O. and M. Totrov. 2005. Vacuuming the periplasm. J Bacteriol 187:1879-83.
5. 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 1:107-25.
6. Zgurskaya, H. I. and H. Nikaido. 2002. Mechanistic parallels in bacterial and human multidrug efflux transporters. Curr Protein Pept Sci 3:531-40.
7. Ko, D. C., M. D. Gordon, J. Y. Jin, and M. P. Scott. 2001. Dynamic movements of organelles containing Niemann-Pick C1 protein: NPC1 involvement in late endocytic events. Mol Biol Cell 12:601-14.
8. Bale, A. E. and K. P. Yu. 2001. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet 10:757-62.
9. Murakami, S., R. Nakashima, E. Yamashita, T. Matsumoto, and A. Yamaguchi. 2006. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443:173-9.
10. Murakami, S., R. Nakashima, E. Yamashita, and A. Yamaguchi. 2002. Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419:587-93.
11. Seeger, M. A., A. Schiefner, T. Eicher, F. Verrey, K. Diederichs, and K. M. Pos. 2006. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313:1295-8.
12. Su, C. C., M. Li, R. Gu, Y. Takatsuka, G. McDermott, H. Nikaido, and E. W. Yu. 2006. Conformation of the AcrB multidrug efflux pump in mutants of the putative proton relay pathway. J Bacteriol 188:7290-6.
13. Yu, E. W., J. R. Aires, G. McDermott, and H. Nikaido. 2005. A periplasmic drugbinding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study. J Bacteriol 187:6804-15.
14. Yu, E. W., G. McDermott, H. I. Zgurskaya, H. Nikaido, and D. E. Koshland, Jr. 2003. Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 300:976-80.
15. Akama, H., M. Kanemaki, M. Yoshimura, T., et al. 2004. Crystal structure of the drug discharge outer membrane protein, OprM, of Pseudomonas aeruginosa : dual modes of membrane anchoring and occluded cavity end. J Biol Chem 279:52816-9.
16. 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 279:25939-42.
17. Higgins, M. K., E. Bokma, E. Koronakis, C. Hughes, and V. Koronakis. 2004. Structure of the periplasmic component of a bacterial drug efflux pump. Proc Natl Acad Sci USA 101:9994-9.
18. 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 405:914-9.
19. Mikolosko, J., K. Bobyk, H. I. Zgurskaya, and P. Ghosh. 2006. Conformational flexibility in the multidrug efflux system protein AcrA. Structure 14:577-87.
20. Grkovic, S., M. H. Brown, and R. A. Skurray. 2002. Regulation of bacterial drug export systems. Microbiol Mol Biol Rev 66:671-701, table of contents.
21. Grkovic, S., M. H. Brown, and R. A. Skurray. 2001. Transcriptional regulation of multidrug efflux pumps in bacteria. Semin Cell Dev Biol 12:225-37.
22. Miller, P. F. and M. C. Sulavik. 1996. Overlaps and parallels in the regulation of intrinsic multiple-antibiotic resistance in Escherichia coli. Mol Microbiol 21:441-8.
23. Poole, K. and R. Srikumar. 2001. Multidrug efflux in Pseudomonas aeruginosa :components, mechanisms and clinical significance. Curr Top Med Chem 1:59-71.
24. Piddock, L. J. 2006. Multidrug-resistance efflux pumps-not just for resistance. Nat Rev Microbiol 4:629-36.
25. Aendekerk, S., S. P. Diggle, Z. Song, N. Hoiby, P. Cornelis, P. Williams, and M. Camara. 2005. The MexGHI-OpmD multidrug efflux pump controls growth, antibiotic susceptibility and virulence in Pseudomonas aeruginosa via 4-quinolone-dependent cell-tocell communication. Microbiology 151:1113-25.
26. Chan, Y. Y. and K. L. Chua. 2005. The Burkholderia pseudomallei BpeAB-OprB efflux pump: expression and impact on quorum sensing and virulence. J Bacteriol 187:4707-19.
27. Domenech, P., M. B. Reed, and C. E. Barry III. 2005. Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect Immun 73:3492-501.
28. Poole, K. 2004. Efflux-mediated multiresistance in Gram-negative bacteria. Clin Microbiol Infect 10:12-26.
29. Zgurskaya, H. I. 2002. Molecular analysis of efflux pump-based antibiotic resistance. Int J Med Microbiol 292:95-105.
30. Nikaido, H. 2001. Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol 12:215-23.
31. Federici, L., D. Du, F. Walas, H. Matsumura, J. Fernandez-Recio, K. S. McKeegan, M. I. Borges-Walmsley, B. F. Luisi, and A. R. Walmsley. 2005. The crystal structure of the outer membrane protein VceC from the bacterial pathogen Vibrio cholerae at 1.8 Å resolution. J Biol Chem 280:15307-14.
32. Tikhonova, E. B. and H. I. Zgurskaya. 2004. AcrA, AcrB, and TolC of Escherichia coli form a stable intermembrane multidrug efflux complex. J Biol Chem 279:32116-24.
33. Touze, T., J. Eswaran, E. Bokma, E. Koronakis, C. Hughes, and V. Koronakis. 2004. Interactions underlying assembly of the Escherichia coli AcrAB-TolC multidrug efflux system. Mol Microbiol 53:697-706.
34. Bokma, E., E. Koronakis, S. Lobedanz, C. Hughes, and V. Koronakis. 2006. Directed evolution of a bacterial efflux pump: Adaptation of the E. coli TolC exit duct to the Pseudomonas MexAB translocase. FEBS Lett 580:5339-43.
35. 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 278:50474-82.
36. Fernandez-Recio, J., F. Walas, L. Federici, J. Venkatesh Pratap, V. N. Bavro, R. N. Miguel, K. Mizuguchi, and B. Luisi. 2004. A model of a transmembrane drug-efflux pump from Gram-negative bacteria. FEBS Letters 578:5-9.
37. Zgurskaya, H. I. and H. Nikaido. 1999. AcrA is a highly asymmetric protein capable of spanning the periplasm. J Mol Biol 285:409-420.
38. 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 182:4264-7.
39. 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 187:1923-9.
40. 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 185:5349-56.
41. 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.
42. Tikhonova, E. B., Q. Wang, and H. I. Zgurskaya. 2002. Chimeric analysis of the multicomponent multidrug efflux transporters from Gram-negative bacteria. J Bacteriol 184:6499-507.
43. 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 185:5657-64.
44. Hearn, E. M., M. R. Gray, and J. M. Foght. 2006. Mutations in the central cavity and periplasmic domain affect efflux activity of the resistance-nodulation-division pump EmhB from Pseudomonas fluorescens cLP6a. J Bacteriol 188:115-23.
45. Middlemiss, J. K. and K. Poole. 2004. Differential impact of MexB mutations on substrate selectivity of the MexAB-OprM multidrug efflux pump of Pseudomonas aeruginosa. J Bacteriol 186:1258-69.
46. Heldwein, E. E. and R. G. Brennan. 2001. Crystal structure of the transcription activator BmrR bound to DNA and a drug. Nature 409:378-82.
47. Zheleznova, E. E., P. N. Markham, A. A. Neyfakh, and R. G. Brennan. 1999. Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter. Cell 96:353-62.
48. Grkovic, S., K. M. Hardie, M. H. Brown, and R. A. Skurray. 2003. Interactions of the QacR multidrug-binding protein with structurally diverse ligands: implications for the evolution of the binding pocket. Biochemistry 42:15226-36.
49. Schumacher, M. A., M. C. Miller, and R. G. Brennan. 2004. Structural mechanism of the simultaneous binding of two drugs to a multidrug-binding protein. EMBO J 23:2923-30.
50. Watkins, R. E., G. B. Wisely, L. B. Moore, J. L., et al. 2001. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292:2329-33.
51. Loo, T. W., M. C. Bartlett, and D. M. Clarke. 2003. Simultaneous binding of two different drugs in the binding pocket of the human multidrug resistance P-glycoprotein. J Biol Chem 278:39706-10.
52. Loo, T. W., M. C. Bartlett, and D. M. Clarke. 2003. Substrate-induced conformational changes in the transmembrane segments of human P-glycoprotein. Direct evidence for the substrate-induced fit mechanism for drug binding. J Biol Chem 278:13603-6.
53. Dawson, R. J. and K. P. Locher. 2006. Structure of a bacterial multidrug ABC transporter. Nature 443:180-5.
54. Loo, T. W. and D. M. Clarke. 2005. Recent progress in understanding the mechanism of P-glycoprotein-mediated drug efflux. J Membr Biol 206:173-85.
55. Pleban, K., S. Kopp, E. Csaszar, M. Peer, T. Hrebicek, A. Rizzi, G. F. Ecker, and P. Chiba. 2005. P-glycoprotein substrate binding domains are located at the transmembrane domain/transmembrane domain interfaces: a combined photoaffinity labelingprotein homology modeling approach. Mol Pharmacol 67:365-74.
56. Rosenberg, M. F., G. Velarde, R. C. Ford, C., et al. 2001. Repacking of the transmembrane domains of P-glycoprotein during the transport ATPase cycle. EMBO J 20:5615-25.
57. Goldberg, M., T. Pribyl, S. Juhnke, and D. H. Nies. 1999. Energetics and topology of CzcA, a cation/proton antiporter of the resistance-nodulation-cell division protein family. J Biol Chem 274:26065-70.
58. Takatsuka, Y. and H. Nikaido. 2006. Threonine-978 in the transmembrane segment of the multidrug efflux pump AcrB of Escherichia coli is crucial for drug transport as a probable component of the proton relay network. J Bacteriol 188:7284-9.
59. Bush, K. 2004. Antibacterial drug discovery in the 21st century. Clin Microbiol Infect 10 Suppl 4:10-7.
60. Spellberg, B., J. H. Powers, E. P. Brass, L. G. Miller, and J. E. Edwards, Jr. 2004. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 38:1279-86.
61. Bush, K., M. Macielag, and M. Weidner-Wells. 2004. Taking inventory: antibacterial agents currently at or beyond phase 1. Curr Opin Microbiol 7:466-76.
62. Barrett, J. and T. Dougherty. 2004. Antibacterial drug discovery and development summit. Expert Opin Investig Drugs 13:715-21.
63. Rothstein, D., S. Mullin, K. Sirokman, C. Hazlett, A. Doye, J. Gwathmey, J. Van Duzer, and C. Murphy. 2004. Presented at the 44th Interscience Conference on Anti microbial Agents and Chemotherapy, Washington, DC.
64. Park, C., J. Blais, S. Lopez, M., et al. 2004. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC.
65. Mani, N., D. Stamos, A. Grillot, J. Parsons, C. Gross, P. Charifson, and T. Grossman. 2004. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC.
66. Bardouniotis, E., R. Thaladaka, N. Walsh, M. Dorsey, M. Schmid, and N. Kaplan. 2004. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC.
67. Overbye, K. and J. Barrett. 2005. Antibiotics: Where did we go wrong? Drug Discov Today 10:45-52.
68. Silver, L. 2005. A retrospective on the failures and successes of antibacterial drug discovery. IDrugs 8:651-655.
69. Ali, S., A. Gill, and A. Lewendon. 2002. Novel targets for antibiotic drug design. Curr Opin Investig Drugs 3:1712-7.
70. Rogers, B. 2004. Bacterial targets to antimicrobial leads and development candidates. Curr Opin Drug Discov Devel 7:211-22.
71. Meyer, A. L. 2005. Prospects and challenges of developing new agents for tough Gramnegatives. Curr Opin Pharmacol 5:490-94.
72. Hoban, D. J., S. K. Bouchillon, B. M. Johnson, J. L. Johnson, and M. J. Dowzicky. 2005. In vitro activity of tigecycline against 6792 Gram-negative and Gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST Program, 2004). Diagn Microbiol Infect Dis 52:215-27.
73. Noskin, G. A. 2005. Tigecycline: a new glycylcycline for treatment of serious infections. Clin Infect Dis 41 Suppl 5:S303-14.
74. Chen, Y., E. Garber, Q. Zhao, Y. Ge, M. A. Wikler, K. Kaniga, and L. Saiman. 2005. In vitro activity of doripenem (S-4661) against multidrug-resistant Gram-negative bacilli isolated from patients with cystic fibrosis. Antimicrob Agents Chemother 49:2510-1.
75. Mushtaq, S., Y. Ge, and D. M. Livermore. 2004. Doripenem versus Pseudomonas aeruginosa in vitro : activity against characterized isolates, mutants, and transconjugants and resistance selection potential. Antimicrob Agents Chemother 48:3086-92.
76. Poole, K. 2005. Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 56:20-51.
77. Rossolini, G. M. and E. Mantengoli. 2005. Treatment and control of severe infections caused by multiresistant Pseudomonas aeruginosa. Clin Microbiol Infect 11 Suppl 4:17-32.
78. Harding, I. and I. Simpson. 2000. Fluoroquinolones: is there a different mechanism of action and resistance against Streptococcus pneumoniae? J Chemother 12 Suppl 4:7-15.
79. Hooper, D. C. 2000. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis 31 Suppl 2:S24-8.
80. Ince, D. and D. C. Hooper. 2001. Mechanisms and frequency of resistance to gatifloxacin in comparison to AM-1121 and ciprofloxacin in Staphylococcus aureus. Antimicrob Agents Chemother 45:2755-64.
81. Ince, D., X. Zhang, L. C. Silver, and D. C. Hooper. 2002. Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone. Antimicrob Agents Chemother 46:3370-80.
82. Ince, D., X. Zhang, L. C. Silver, and D. C. Hooper. 2003. Topoisomerase targeting with and resistance to gemifloxacin in Staphylococcus aureus. Antimicrob Agents Chemother 47:274-82.
83. Jacobs, M. R., S. Bajaksouzian, A. Windau, P. C., et al. 2004. In vitro activity of the new quinolone WCK 771 against staphylococci. Antimicrob Agents Chemother 48:3338-42.
84. Yu, J. L., L. Grinius, and D. C. Hooper. 2002. NorA functions as a multidrug efflux protein in both cytoplasmic membrane vesicles and reconstituted proteoliposomes. J Bacteriol 184:1370-7.
85. Fritsche, T. R., P. A. Strabala, H. S. Sader, M. J. Dowzicky, and R. N. Jones. 2005. Activity of tigecycline tested against a global collection of Enterobacteriaceae, including tetracycline-resistant isolates. Diagn Microbiol Infect Dis 52:209-13.
86. Zhanel, G. G., K. Homenuik, K. Nichol, A., et al. 2004. The glycylcyclines: a comparative review with the tetracyclines. Drugs 64:63-88.
87. Weir, S., A. Macone, J. Donatelli, C. Trieber, D. Taylor, S. Tanaka, and S. Levy. 2003. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL.
88. Lomovskaya, O., M. S. Warren, A., Lee, J., et al. 2001. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa : novel agents for combination therapy. Antimicrob Agents Chemother 45:105-16.
89. Warren, M., J. C. Lee, A. Lee, K. Hoshino, H. Ishida, and O. Lomovskaya. 2000. Presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada.
90. Renau, T. E., R. Leger, L. Filonova, E. M., et al. 2003. Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg Med Chem Lett 13:2755-8.
91. Renau, T. E., R. Leger, R. Yen, M. W., et al. 2002. Peptidomimetics of efflux pump inhibitors potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg Med Chem Lett 12:763-6.
92. 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 43:2624-8.
93. 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 44:3322-7.
94. Okamoto, K., N. Gotoh, and T. Nishino. 2002. Extrusion of penem antibiotics by multicomponent efflux systems MexAB-OprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa. Antimicrob Agents Chemother 46:2696-9.
95. Nakayama, K., Y. Ishida, M. Ohtsuka, H., et al. 2003. MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization. Bioorg Med Chem Lett 13:4201-4.
96. Nakayama, K., Y. Ishida, M. Ohtsuka, H., et al. 2003. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: achieving activity in vivo through the use of alternative scaffolds. Bioorg Med Chem Lett 13:4205-8.
97. Nakayama, K., H. Kawato, J. Watanabe, M., et al. 2004. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 3: Optimization of potency in the pyridopyrimidine series through the application of a pharmacophore model. Bioorg Med Chem Lett 14:475-9.
98. Nakayama, K., N. Kuru, M. Ohtsuka, Y., et al. 2004. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 4: Addressing the problem of poor stability due to photoisomerization of an acrylic acid moiety. Bioorg Med Chem Lett 14:2493-7.
99. Kaatz, G. W. 2005. Bacterial efflux pump inhibition. Curr Opin Investig Drugs 6:191-8.
100. Lomovskaya, O. and W. Watkins. 2001. Inhibition of efflux pumps as a novel approach to combat drug resistance in bacteria. J Mol Microbiol Biotechnol 3:225-36.
101. Marquez, B. 2005. Bacterial efflux systems and efflux pumps inhibitors. Biochimie 87:1137-47.
102. Pages, J. M., M. Masi, and J. Barbe. 2005. Inhibitors of efflux pumps in Gram-negative bacteria. Trends Mol Med 11:382-9.
103. Renau, T. E., R. Leger, E. M. Flamme, M. W., et al. 2001. Addressing the stability of C-capped dipeptide efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg Med Chem Lett 11:663-7.
104. Watkins, W. J., Y. Landaverry, R. Leger, R., et al. 2003. The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors. Bioorg Med Chem Lett 13:4241-4.
105. Baucheron, S., C. Mouline, K. Praud, E. Chaslus-Dancla, and A. Cloeckaert. 2005. TolC but not AcrB is essential for multidrug-resistant Salmonella enterica serotype Typhimurium colonization of chicks. J Antimicrob Chemother 55:707-12.
106. Giraud, E., G. Blanc, A. Bouju-Albert, F. X. Weill, and C. Donnay-Moreno. 2004. Mechanisms of quinolone resistance and clonal relationship among Aeromonas salmonicida strains isolated from reared fish with furunculosis. J Med Microbiol 53:895-901.
107. Hasdemir, U. O., J. Chevalier, P. Nordmann, and J. M. Pages. 2004. Detection and prevalence of active drug efflux mechanism in various multidrug-resistant Klebsiella pneumoniae strains from Turkey. J Clin Microbiol 42:2701-6.
108. Kriengkauykiat, J., E. Porter, O. Lomovskaya, and A. Wong-Beringer. 2005. Use of an efflux pump inhibitor to determine the prevalence of efflux pump-mediated fluoroquinolone resistance and multidrug resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 49:565-70.
109. Mamelli, L., J. P. Amoros, J. M. Pages, and J. M. Bolla. 2003. A phenylalanine-arginine beta-naphthylamide sensitive multidrug efflux pump involved in intrinsic and acquired resistance of Campylobacter to macrolides. Int J Antimicrob Agents 22:237-41.
110. Mamelli, L., V. Prouzet-Mauleon, J. M. Pages, F. Megraud, and J. M. Bolla. 2005. Molecular basis of macrolide resistance in Campylobacter : role of efflux pumps and target mutations. J Antimicrob Chemother 56:491-97.
111. Payot, S., L. Avrain, C. Magras, K. Praud, A. Cloeckaert, and E. Chaslus-Dancla. 2004. Relative contribution of target gene mutation and efflux to fluoroquinolone and erythromycin resistance, in French poultry and pig isolates of Campylobacter coli. Int J Antimicrob Agents 23:468-72.
112. Payot, S., A. Cloeckaert, and E. Chaslus-Dancla. 2002. Selection and characterization of fluoroquinolone-resistant mutants of Campylobacter jejuni using enrofloxacin. Microb Drug Resist 8:335-43.
113. Saenz, Y., J. Ruiz, M. Zarazaga, M. Teixido, C. Torres, and J. Vila. 2004. Effect of the efflux pump inhibitor Phe-Arg-beta-naphthylamide on the MIC values of the quinolones, tetracycline and chloramphenicol, in Escherichia coli isolates of different origin. J Antimicrob Chemother 53:544-5.
114. Thorarensen, A., A. L. Presley-Bodnar, K. R. Marotti, T. P., et al. 2001. 3-Arylpiperidines as potentiators of existing antibacterial agents. Bioorg Med Chem Lett 11:1903-6.
115. Bohnert, J. A. and W. V. Kern. 2005. Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob Agents Chemother 49:849-52.
116. Chevalier, J., S. Atifi, A. Eyraud, A. Mahamoud, J. Barbe, and J. M. Pages. 2001. New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains. J Med Chem 44:4023-6.
117. Chevalier, J., J. Bredin, A. Mahamoud, M. Mallea, J. Barbe, and J. M. Pages. 2004. Inhibitors of antibiotic efflux in resistant Enterobacter aerogenes and Klebsiella pneumoniae strains. Antimicrob Agents Chemother 48:1043-6.
118. Gallo, S., J. Chevalier, A. Mahamoud, A. Eyraud, J. M. Pages, and J. Barbe. 2003. 4-alkoxy and 4-thioalkoxyquinoline derivatives as chemosensitizers for the chloramphenicol-resistant clinical Enterobacter aerogenes 27 strain. Int J Antimicrob Agents 22:270-3.
119. Mallea, M., A. Mahamoud, J. Chevalier, S. Alibert-Franco, P. Brouant, J. Barbe, and J. M. Pages. 2003. Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates. Biochem J 376:801-5.
120. Fojo, T. and S. Bates. 2003. Strategies for reversing drug resistance. Oncogene 22:7512-23.
121. Liang, X. J. and A. Aszalos. 2006. Multidrug transporters as drug targets. Curr Drug Targets 7:911-21.
122. Pleban, K., D. Kaiser, S. Kopp, M. Peer, P. Chiba, and G. F. Ecker. 2005. Targeting drug-efflux pumps-a pharmacoinformatic approach. Acta Biochim Pol 52:737-40.
123. Szakacs, G., J. K. Paterson, J. A. Ludwig, C. Booth-Genthe, and M. M. Gottesman. 2006. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219-34.
124. Teodori, E., S. Dei, C. Martelli, S. Scapecchi, and F. Gualtieri. 2006. The functions and structure of ABC transporters: implications for the design of new inhibitors of Pgp and MRP1 to control multidrug resistance (MDR). Curr Drug Targets 7:893-909.
125. Teodori, E., S. Dei, S. Scapecchi, and F. Gualtieri. 2002. The medicinal chemistry of multidrug resistance (MDR) reversing drugs. Farmaco 57:385-415.
126. Yoshida, K., K. Nakayama, N. Kuru, S., et al. 2006. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 5: Carbon-substituted analogues at the C-2 position. Bioorg Med Chem 14:1993-2004.
127. Yoshida, K. I., K. Nakayama, Y. Yokomizo, M., et al. 2006. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: Exploration of aromatic substituents. Bioorg Med Chem 14:8506-18.
128. Mallea, M., J. Chevalier, A. Eyraud, and J. M. Pages. 2002. Inhibitors of antibiotic efflux pump in resistant Enterobacter aerogenes strains. Biochem Biophys Res Commun 293:1370-3.
129. Lomovskaya, O. and K. A. Bostian. 2006. Practical applications and feasibility of efflux pump inhibitors in the clinic-A vision for applied use. Biochem Pharmacol 71:910-18.
130. Sauna, Z. E., M. B. Andrus, T. M. Turner, and S. V. Ambudkar. 2004. Biochemical basis of polyvalency as a strategy for enhancing the efficacy of P-glycoprotein (ABCB1) modulators: stipiamide homodimers separated with defined-length spacers reverse drug efflux with greater efficacy. Biochemistry 43:2262-71.
131. Amin, A. H., T. V. Subbaiah, and K. M. Abbasi. 1969. Berberine sulfate: antimicrobial activity, bioassay, and mode of action. Can J Microbiol 15:1067-1076.
132. Severina, I. I., M. S. Muntyan, K. Lewis, and V. P. Skulachev. 2001. Transfer of cationic antibacterial agents berberine, palmatine and benzalkonium through bimolecular planar phospholipid film and Staphylococcus aureus membrane. IUBMB-Life Sciences 52:321-324.
133. Hsieh, P. C., S. A. Siegel, B. Rogers, D. Davis, and K. Lewis. 1998. Bacteria lacking a multidrug pump: a sensitive tool for drug discovery. Proc Natl Acad Sci USA 95:6602-6.
134. Lewis, K. 2001. In search of natural substrates and inhibitors of MDR pumps. J Mol Microbiol Biotechnol 3:247-54.
135. Stermitz, F. R., P. Lorenz, J. N. Tawara, L. Zenewicz, and K. Lewis. 2000a. Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA 97:1433-7.
136. Tegos, G., F. R. Stermitz, O. Lomovskaya, and K. Lewis. 2002. Multidrug pump inhibitors uncover the remarkable activity of plant antimicrobials. Antimicrob Agents Chemother 46:3133-41.
137. Belofsky, G., R. Carreno, K. Lewis, A. Ball, G. Casadei, and G. P. Tegos. 2006. Metabolites of the “smoke tree,” Dalea spinosa, potentiate antibiotic activity against multidrug-resistant Staphylococcus aureus. J Nat Prod 69:261-4.
138. Belofsky, G., D. Percivill, K. Lewis, G. P. Tegos, and J. Ekart. 2004. Phenolic metabolites of Dalea versicolor that enhance antibiotic activity against model pathogenic bacteria. J Nat Prod 67:481-4.
139. Morel, C., F. R. Stermitz, G. Tegos, and K. Lewis. 2003. Isoflavone MDR efflux pump inhibitors from Lupinus argenteus. Synergism between some antibiotics and isoflavones. J Agricult Food Chem 51: 5677-9.
140. Stermitz, F. R., K. K. Cashmana, K. M. Halligana, C. Morel, G. P. Tegos, and K. Lewis. 2003. Polyacylated neohesperidosides from Geranium caespitosum : bacterial multidrug resistance pump inhibitors. Bioorg Med Chem Lett 13:1915-8.
141. Stermitz, F. R., L. N. Scriven, G. Tegos, and K. Lewis. 2002. Two flavonols from Artemisia annua which potentiate the activity of berberine and norfloxacin against a resistant strain of Staphylococcus aureus. Planta Med 68:1140-1.
142. Ball, A. R., G. Casadei, S. Samosorn, J. B. Bremner, F. M. Ausubel, T. I. Moy, and K. Lewis. 2006. Conjugating berberine to an MDR pump inhibitor creates an effective antimicrobial. ACS Chem Biol 1:594-600.
143. Moy, T. I., A. R. Ball, Z. Anklesaria, G. Casadei, K. Lewis, and F. M. Ausubel. 2006. Identification of novel antimicrobials using a live-animal infection model. Proc Natl Acad Sci USA 103:10414-9.
144. Milovic, N. M., J. Wang, K. Lewis, and A. M. Klibanov. 2005. Immobilized N -alkylated polyethylenimine avidly kills bacteria by rupturing cell membranes with no resistance developed. Biotechnol Bioeng 90:715-22.
145. Tiller, J. C., C. J. Liao, K. Lewis, and A. M. Klibanov. 2001. Designing surfaces that kill bacteria on contact. Proc Natl Acad Sci USA 98:5981-5.
146. Lin, J., J. C. Tiller, S. B. Lee, K. Lewis, and A. M. Klibanov. 2002. Insights into bactericidal action of surface-attached poly(vinyl-N -hexylpyridinium) chains. Biotechnol Lett 24:801-805.
147. Lewis, K. and A. M. Klibanov. 2005. Surpassing nature: rational design of sterilesurface materials. Trends Biotechnol 23:343-8.