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  • Review Article
  • Published:

Waltzing transporters and 'the dance macabre' between humans and bacteria

Nature Reviews Drug Discovery volume 6, pages 56–65 (2007)Cite this article

Key Points

  • Multidrug-resistance (MDR) efflux pumps are membrane transporter proteins that have a broad-spectrum of substrate specificity.

  • Most classes of currently available antibiotics and compounds in development are considered to be 'Gram-positive only' and do not have clinical efficacy against Gram-negative bacteria.

  • High intrinsic resistance results from the combination of efflux by MDR pumps and the low permeability of the outer membrane.

  • MDR pumps from the resistance-nodulation-cell-division (RND) family are the main components of cellular defense against antibiotics; they have an unprecedented breadth of substrate promiscuity.

  • The inner membrane RND in combination with the periplasmic 'adaptor' protein and the outer membrane channel extrude their substrates across the whole cellular envelope directly into the medium, a phenomenon referred to as trans-envelope transport.

  • High-resolution structures have been determined for all the components of the tri-partite complex and provide the structural basis for understanding trans-envelope transport.

  • RND transporters have a voluminous substrate-binding pocket that can accommodate a variety of substrates; this binding pocket is located in the large periplasmic domain of the pump.

  • RND transporters function as trimers, with each monomer sequentially alternating through three phases of the efflux process: access, binding and extrusion.

  • Elucidation of structure and transport mechanisms provides for multiple opportunities for the design of efflux pump inhibitors.

  • Inhibition of efflux pumps in bacteria will significantly improve the effectiveness of antibacterial therapy.

Abstract

Multidrug-resistance efflux pumps — in particular those belonging to the resistance-nodulation-cell-division (RND) family of transporters, with their unusually high degree of substrate promiscuity — significantly restrict the effectiveness of antibacterial therapy. Recent years have heralded remarkable insights into the structure and mechanisms of these fascinating molecular machines. Here, we review recent advances in the field and describe various approaches used in combating efflux-mediated resistance.

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Figure 1: Structure of AcrA, AcrB and TolC proteins from Escherichia coli.
Figure 2: Fitted model of the Escherichia coli AcrAB–TolC tri-partite efflux complex.
Figure 3: Structure of AcrB based on the asymmetric crystal.
Figure 4: Various inhibitors of RND transporters.

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References

  1. Teodori, E., Dei, S., Martelli, C., Scapecchi, S. & Gualtieri, F. 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 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Leonard, G. D., Fojo, T. & Bates, S. E. The role of ABC transporters in clinical practice. Oncologist 8, 411–424 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Gottesman, M. M., Fojo, T. & Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nature Rev. Cancer 2, 48–58 (2002).

    Article  CAS  Google Scholar 

  4. Prasad, R., Gaur, N. A., Gaur, M. & Komath, S. S. Efflux pumps in drug resistance of Candida. Infect. Disord. Drug Targets 6, 69–83 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Jones, P. M. & George, A. M. Multidrug resistance in parasites: ABC transporters, P-glycoproteins and molecular modelling. Int. J. Parasitol. 35, 555–566 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Poole, K. Efflux-mediated antimicrobial resistance. J. Antimicrob. Chemother. 56, 20–51 (2005). The comprehensive review on clinically relevant bacterial multidrug-resistance efflux pumps

    Article  CAS  PubMed  Google Scholar 

  7. Piddock, L. J. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin. Microbiol. Rev. 19, 382–402 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Paulsen, I. T., Chen, J., Nelson, K. E. & Saier, M. H., Jr. Comparative genomics of microbial drug efflux systems. J. Mol. Microbiol. Biotechnol. 3, 145–150 (2001).

    CAS  PubMed  Google Scholar 

  9. Chung, Y. J. & Saier, M. H., Jr. SMR-type multidrug resistance pumps. Curr. Opin. Drug Discov. Devel. 4, 237–245 (2001).

    CAS  PubMed  Google Scholar 

  10. Saier, M. H., Jr. & Paulsen, I. T. Phylogeny of multidrug transporters. Semin. Cell Dev. Biol. 12, 205–213 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Saier, M. H., Jr. et al. The major facilitator superfamily. J. Mol. Microbiol. Biotechnol. 1, 257–279 (1999).

    CAS  PubMed  Google Scholar 

  12. Tseng, T. T. et al. The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J. Mol. Microbiol. Biotechnol. 1, 107–125 (1999). A comprehensive phylogenetic analysis of the RND superfamily of proteins. This study identified Niemann–Pick type C protein as a member of the RND family with the putative transporter function.

    CAS  PubMed  Google Scholar 

  13. Saier, M. H., Jr. et al. Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria. FASEB J. 12, 265–274 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Neyfakh, A. A. The ostensible paradox of multidrug recognition. J Mol Microbiol Biotechnol 3, 151–154 (2001). This review formulated principles of a flexible multidrug-binding pocket.

    CAS  PubMed  Google Scholar 

  15. Vazquez-Laslop, N., Zheleznova, E. E., Markham, P. N., Brennan, R. G. & Neyfakh, A. A. Recognition of multiple drugs by a single protein: a trivial solution of an old paradox. Biochem. Soc. Trans. 28, 517–520 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Nikaido, H. Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin. Cell. Dev. Biol. 12, 215–223 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Zgurskaya, H. I. & Nikaido, H. Multidrug resistance mechanisms: drug efflux across two membranes. Mol. Microbiol. 37, 219–225 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Rello, J. Bench-to-bedside review: Therapeutic options and issues in the management of ventilator-associated bacterial pneumonia. Crit. Care 9, 259–265 (2005).

    Article  PubMed  Google Scholar 

  19. De Kievit, T. R. et al. Multidrug Efflux Pumps: expression patterns and contribution to antibiotic resistance in Pseudomonas aeruginosa biofilms. Antimicrob. Agents Chemother. 45, 1761–1770 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Markham, P. N. Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. Antimicrob. Agents Chemother. 43, 988–989 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lomovskaya, O. et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob. Agents Chemother. 45, 105–116 (2001). This study describes the first class of broad-spectrum efflux-pump inhibitors targeting RND proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Oethinger, M., Kern, W. V., Jellen-Ritter, A. S., McMurry, L. M. & Levy, S. B. Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump. Antimicrob. Agents Chemother. 44, 10–13 (2000). This study demonstrated that a combination of efflux and target mutations are essential for high levels of resistance to fluoroquinolones.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lomovskaya, O. & Bostian, K. A. Practical applications and feasibility of efflux pump inhibitors in the clinic — a vision for applied use. Biochem. Pharmacol. 71, 910–918 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Lewis, K. Multidrug resistance: versatile drug sensors of bacterial cells. Curr. Biol. 9, R403–R407 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Lomovskaya, O. & Watkins, W. Inhibition of efflux pumps as a novel approach to combat drug resistance in bacteria. J. Mol. Microbiol. Biotechnol. 3, 225–236 (2001).

    CAS  PubMed  Google Scholar 

  26. Lomovskaya, O. & Watkins, W. J. Efflux pumps: their role in antibacterial drug discovery. Curr. Med. Chem. 8, 1699–1711 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Nikaido, H. Molecular basis of bacterial outer membrane permeability revisited. Microbiol. Mol. Biol. Rev. 67, 593–656 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nikaido, H., Basina, M., Nguyen, V. & Rosenberg, E. Y. Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those b-lactam antibiotics containing lipophilic side chains. J. Bacteriol. 180, 4686–4692 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Sanchez, L., Pan, W., Vinas, M. & Nikaido, H. The AcrAB homolog of Haemophilus influenzae codes for a functional multidrug efflux pump. J. Bacteriol. 179, 6855–6857 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sen, K., Hellman, J. & Nikaido, H. Porin channels in intact cells of Escherichia coli are not affected by Donnan potentials across the outer membrane. J. Biol. Chem. 263, 1182–1187 (1988).

    CAS  PubMed  Google Scholar 

  31. Lomovskaya, O. & Totrov, M. Vacuuming the periplasm. J. Bacteriol. 187, 1879–1883 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zgurskaya, H. I. & Nikaido, H. Mechanistic parallels in bacterial and human multidrug efflux transporters. Curr. Protein. Pept. Sci. 3, 531–540 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Ko, D. C., Gordon, M. D., Jin, J. Y. & Scott, M. P. Dynamic movements of organelles containing Niemann-Pick C1 protein: NPC1 involvement in late endocytic events. Mol. Biol. Cell 12, 601–614 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bale, A. E. & Yu, K. P. The hedgehog pathway and basal cell carcinomas. Hum. Mol. Genet. 10, 757–762 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Murakami, S., Nakashima, R., Yamashita, E. & Yamaguchi, A. Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419, 587–593 (2002). First high-resolution structure of multidrug transporter driven by proton-motive force.

    Article  CAS  PubMed  Google Scholar 

  36. Yu, E. W., Aires, J. R., McDermott, G. & Nikaido, H. A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study. J. Bacteriol. 187, 6804–6815 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yu, E. W., McDermott, G., Zgurskaya, H. I., Nikaido, H. & Koshland, D. E., Jr. Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 300, 976–980 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Su, C. C. et al. Conformation of the AcrB multidrug efflux pump in mutants of the putative proton relay pathway. J. Bacteriol. 188, 7290–7296 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Murakami, S., Nakashima, R., Yamashita, E., Matsumoto, T. & Yamaguchi, A. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443, 173–179 (2006). This study and Seeger et al . suggested that the AcrB mechanism might involve cycling through three consecutive conformations, with substrate trapped in one of the conformers.

    Article  CAS  PubMed  Google Scholar 

  40. Seeger, M. A. et al. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313, 1295–1298 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Mikolosko, J., Bobyk, K., Zgurskaya, H. I. & Ghosh, P. Conformational flexibility in the multidrug efflux system protein AcrA. Structure 14, 577–587 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Akama, H. et al. Crystal structure of the membrane fusion protein, MexA, of the multidrug transporter in Pseudomonas aeruginosa. J. Biol. Chem. 279, 25939–25942 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Higgins, M. K., Bokma, E., Koronakis, E., Hughes, C. & Koronakis, V. Structure of the periplasmic component of a bacterial drug efflux pump. Proc. Natl Acad. Sci. USA 101, 9994–9999 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Akama, H. et al. 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, 52816–52819 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Koronakis, V., Sharff, A., Koronakis, E., Luisi, B. & Hughes, C. Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature 405, 914–919 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Miller, P. F. & Sulavik, M. C. Overlaps and parallels in the regulation of intrinsic multiple-antibiotic resistance in Escherichia coli. Mol. Microbiol. 21, 441–448 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Poole, K. & Srikumar, R. Multidrug efflux in Pseudomonas aeruginosa: components, mechanisms and clinical significance. Curr. Top. Med. Chem. 1, 59–71 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Grkovic, S., Brown, M. H. & Skurray, R. A. Regulation of bacterial drug export systems. Microbiol. Mol. Biol. Rev. 66, 671–701, table of contents (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Grkovic, S., Brown, M. H. & Skurray, R. A. Transcriptional regulation of multidrug efflux pumps in bacteria. Semin. Cell Dev. Biol. 12, 225–237 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Piddock, L. J. Multidrug-resistance efflux pumps- not just for resistance. Nature Rev. Microbiol. 4, 629–636 (2006).

    Article  CAS  Google Scholar 

  51. Aendekerk, S. et al. The MexGHI-OpmD multidrug efflux pump controls growth, antibiotic susceptibility and virulence in Pseudomonas aeruginosa via 4-quinolone-dependent cell-to-cell communication. Microbiology 151, 1113–1125 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Chan, Y. Y. & Chua, K. L. The Burkholderia pseudomallei BpeAB-OprB efflux pump: expression and impact on quorum sensing and virulence. J. Bacteriol. 187, 4707–4719 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Domenech, P., Reed, M. B. & Barry, C. E., 3rd Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect. Immun. 73, 3492–3501 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Poole, K. Efflux-mediated multiresistance in Gram-negative bacteria. Clin. Microbiol. Infect. 10, 12–26 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Zgurskaya, H. I. Molecular analysis of efflux pump-based antibiotic resistance. Int. J. Med. Microbiol. 292, 95–105 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Federici, L. et al. The crystal structure of the outer membrane protein VceC from the bacterial pathogen Vibrio cholerae at 1. 8 Å resolution. J. Biol. Chem. 280, 15307–15314 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Tikhonova, E. B. & Zgurskaya, H. I. AcrA, AcrB, and TolC of Escherichia coli form a stable intermembrane multidrug efflux complex. J. Biol. Chem. 279, 32116–32124 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Touze, T. et al. Interactions underlying assembly of the Escherichia coli AcrAB-TolC multidrug efflux system. Mol. Microbiol. 53, 697–706 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Bokma, E., Koronakis, E., Lobedanz, S., Hughes, C. & Koronakis, V. Directed evolution of a bacterial efflux pump: Adaptation of the E. coli TolC exit duct to the Pseudomonas MexAB translocase. FEBS Lett. 580, 5339–5343 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Ip, H., Stratton, K., Zgurskaya, H. & Liu, J. pH-induced conformational changes of AcrA, the membrane fusion protein of Escherichia coli multidrug efflux system. J. Biol. Chem. 278, 50475–50482 (2003).

    Article  CAS  Google Scholar 

  61. Fernandez-Recio, J. et al. A model of a transmembrane drug-efflux pump from Gram-negative bacteria. FEBS Lett. 578, 5–9 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Zgurskaya, H. I. & Nikaido, H. 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 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zgurskaya, H. I. & Nikaido, H. AcrA is a highly asymmetric protein capable of spanning the periplasm. J. Mol. Biol. 285, 409–420 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Tikhonova, E. B., Wang, Q. & Zgurskaya, H. I. Chimeric analysis of the multicomponent multidrug efflux transporters from Gram-negative bacteria. J. Bacteriol. 184, 6499–6507 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mao, W. et al. 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 (2002). This study and Tikhonova et al . provided genetic evidence that periplasmic domains of RND transporters are involved in substrate binding.

    Article  CAS  PubMed  Google Scholar 

  66. Elkins, C. A. & Nikaido, H. 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 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aires, J. R. & Nikaido, H. Aminoglycosides are captured from both periplasm and cytoplasm by the AcrD multidrug efflux transporter of Escherichia coli. J. Bacteriol. 187, 1923–1929 (2005). This study provides the biochemical evidence of periplasmic capturing by the RND transporters.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yu, E. W., Aires, J. R. & Nikaido, H. 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 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hearn, E. M., Gray, M. R. & Foght, J. M. Mutations in the central cavity and periplasmic domain affect efflux activity of the resistance-nodulation-division pump EmhB from Pseudomonas fluorescens cLP6a. J. Bacteriol. 188, 115–123 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Middlemiss, J. K. & Poole, K. Differential impact of MexB mutations on substrate selectivity of the MexAB-OprM multidrug efflux pump of Pseudomonas aeruginosa. J. Bacteriol. 186, 1258–1269 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zheleznova, E. E., Markham, P. N., Neyfakh, A. A. & Brennan, R. G. Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter. Cell 96, 353–362 (1999). The first crystal structure of a protein capable of multidrug binding. This study had a major influence on current views of multidrug binding pockets.

    Article  CAS  PubMed  Google Scholar 

  72. Heldwein, E. E. & Brennan, R. G. Crystal structure of the transcription activator BmrR bound to DNA and a drug. Nature 409, 378–382 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Grkovic, S., Hardie, K. M., Brown, M. H. & Skurray, R. A. Interactions of the QacR multidrug-binding protein with structurally diverse ligands: implications for the evolution of the binding pocket. Biochemistry 42, 15226–15236 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Schumacher, M. A., Miller, M. C. & Brennan, R. G. Structural mechanism of the simultaneous binding of two drugs to a multidrug-binding protein. EMBO J. 23, 2923–2930 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Watkins, R. E. et al. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292, 2329–2333 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Loo, T. W., Bartlett, M. C. & Clarke, D. M. Simultaneous binding of two different drugs in the binding pocket of the human multidrug resistance P-glycoprotein. J. Biol. Chem. 278, 39706–39710 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Loo, T. W., Bartlett, M. C. & Clarke, D. M. 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, 13603–13606 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Dawson, R. J. & Locher, K. P. Structure of a bacterial multidrug ABC transporter. Nature 443, 180–185 (2006). The first high-resolution structure of a multidrug resistance ABC transporter.

    Article  CAS  PubMed  Google Scholar 

  79. Loo, T. W. & Clarke, D. M. Recent progress in understanding the mechanism of P-glycoprotein-mediated drug efflux. J. Membr. Biol. 206, 173–185 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Pleban, K. et al. P-glycoprotein substrate binding domains are located at the transmembrane domain/transmembrane domain interfaces: a combined photoaffinity labeling-protein homology modeling approach. Mol. Pharmacol. 67, 365–374 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Rosenberg, M. F. et al. Repacking of the transmembrane domains of P-glycoprotein during the transport ATPase cycle. EMBO J. 20, 5615–5625 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Goldberg, M., Pribyl, T., Juhnke, S. & Nies, D. H. Energetics and topology of CzcA, a cation/proton antiporter of the resistance-nodulation-cell division protein family. J. Biol. Chem. 274, 26065–26070 (1999). The pioneering study on the mechanism of RND transport.

    Article  CAS  PubMed  Google Scholar 

  83. Takatsuka, Y. & Nikaido, H. 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, 7284–7289 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C. & Gottesman, M. M. Targeting multidrug resistance in cancer. Nature Rev. Drug Discov. 5, 219–234 (2006).

    Article  CAS  Google Scholar 

  85. Pleban, K. et al. Targeting drug-efflux pumps- a pharmacoinformatic approach. Acta Biochim. Pol. 52, 737–740 (2005).

    CAS  PubMed  Google Scholar 

  86. Liang, X. J. & Aszalos, A. Multidrug transporters as drug targets. Curr. Drug Targets 7, 911–921 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Fojo, T. & Bates, S. Strategies for reversing drug resistance. Oncogene 22, 7512–7523 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Teodori, E., Dei, S., Scapecchi, S. & Gualtieri, F. The medicinal chemistry of multidrug resistance (MDR) reversing drugs. Farmaco. 57, 385–415 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Pages, J. M., Masi, M. & Barbe, J. Inhibitors of efflux pumps in Gram-negative bacteria. Trends Mol. Med. 11, 382–389 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Renau, T. E. et al. Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg. Med. Chem. Lett. 13, 2755–2758 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Watkins, W. J. et al. 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Bohnert, J. A. & Kern, W. V. Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob. Agents. Chemother. 49, 849–852 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Schumacher, A. et al. Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Enterobacteriaceae other than Escherichia coli. J. Antimicrob. Chemother. 57, 344–348 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Nakayama, K. et al. 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Nakayama, K. et al. 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, 4205–4208 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Nakayama, K. et al. 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, 475–479 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Nakayama, K. et al. 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, 2493–2497 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Yoshida, K. et al. 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 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Yoshida, K. I. et al. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 6: Exploration of aromatic substituents. Bioorg. Med. Chem. (2006).

  100. Mallea, M. et al. Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates. Biochem. J. 376, 801–805 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hasdemir, U. O., Chevalier, J., Nordmann, P. & Pages, J. M. Detection and prevalence of active drug efflux mechanism in various multidrug-resistant Klebsiella pneumoniae strains from Turkey. J. Clin. Microbiol. 42, 2701–2706 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mallea, M., Chevalier, J., Eyraud, A. & Pages, J. M. Inhibitors of antibiotic efflux pump in resistant Enterobacter aerogenes strains. Biochem. Biophys. Res. Commun. 293, 1370–1373 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Chevalier, J. et al. New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains. J. Med. Chem. 44, 4023–4026 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Thorarensen, A. et al. 3-Arylpiperidines as potentiators of existing antibacterial agents. Bioorg. Med. Chem. Lett. 11, 1903–1906 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Sauna, Z. E., Andrus, M. B., Turner, T. M. & Ambudkar, S. V. 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, 2262–2271 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This review is written in the memory of Alex Neyfakh (1959–2006). We are grateful to K. Bostian for helpful discussions and for critical reading of the manuscript. The research in H.I.Z's lab is supported by a National Institutes of Health grant.

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Authors and Affiliations

  1. Mpex Pharmaceuticals, Inc., 3030 Bunker Hill Street, Suite 200, San Diego, 92109, California, USA

    Olga Lomovskaya

  2. Department of Chemistry and Biochemistry, University of Oklahoma, 620 Parrington Oval, Room 208, Norman, 73019, Oklahoma, USA

    Helen I. Zgurskaya

  3. Molsoft L.L.C. 3366 North Torrey Pines Court, Suite 300, La Jolla, 92037, California, USA

    Maxim Totrov

  4. Gilead Sciences, 333 Lakeside Drive, Foster City, 04404, California, USA

    William J. Watkins

Authors
  1. Olga Lomovskaya
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  2. Helen I. Zgurskaya
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  3. Maxim Totrov
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  4. William J. Watkins
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Corresponding author

Correspondence to Olga Lomovskaya.

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DATABASES

Protein Data Bank

AcrA

AcrB

MexA

MexAB

Oprm

Sav1866

TolC

VceC

FURTHER INFORMATION

Mpex Pharmaceuticals

Daiichi Pharmaceutical Co Ltd

Antibiotic/Antimicrobial Resistance

Molsoft

Glossary

Nosocomial

Acquired or occurring in a hospital.

RND permease superfamily

The resistance-nodulation-cell-division (RND) family of transporters are found ubiquitously in bacteria, archaea and eukaryotes. In accordance with the Transporter Classification (TC) system (www.tcdb.org]) approved by IUBMB (International Union of Biochemistry and Molecular BiologyY) its TC number is 2.A.6.

Quorum signal molecules

Molecules that are released by the microorganisms as a means of monitoring population density. When these signal molecules reach a threshold concentration, the population density has attained a critical level or quorum, and quorum-dependent genes are expressed.

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Lomovskaya, O., Zgurskaya, H., Totrov, M. et al. Waltzing transporters and 'the dance macabre' between humans and bacteria. Nat Rev Drug Discov 6, 56–65 (2007). https://doi.org/10.1038/nrd2200

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