1887

Abstract

The active efflux of toxic compounds by (multi)drug transporters is one of the mechanisms that bacteria have developed to resist cytotoxic drugs. The authors describe the role of the lactococcal secondary multidrug transporter LmrP in the resistance to a broad range of clinically important antibiotics. Cells expressing LmrP display an increased resistance to the lincosamide, streptogramin, tetracycline and 14- and 15-membered macrolide antibiotics. The streptogramin antibiotic quinupristin, present in the fourth-generation antibiotic RP 59500, can inhibit LmrP-mediated Hoechst 33342 transport, but is not transported by LmrP, indicating that quinupristin acts as a modulator of LmrP activity. LmrP-expressing cells in which a proton-motive force is generated accumulate significantly less tetracycline than control cells without LmrP expression. In contrast, LmrP-expressing and control cells accumulate equal amounts of tetracycline in the absence of metabolic energy. These findings demonstrate that the increased antibiotic resistance in LmrP-expressing cells is a result of the active extrusion of antibiotics from the cell.

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2001-10-01
2020-04-05
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References

  1. Aı́nsa J. A., Blokpoel M. C. J., Otal I., Young D. B., Martı́n C., de Smet K. A. L.. 1998; Molecular cloning and characterization of Tap, a putative multidrug efflux pump present in Mycobacterium fortuitum and Mycobacterium tuberculosis. J Bacteriol180:5836–5843
    [Google Scholar]
  2. Anderson R. M.. 1999; The pandemic of antibiotic resistance. Nat Med5:147–149[CrossRef]
    [Google Scholar]
  3. Aumercier M., Bouhallab S., Capmau M. L., Le Goffic F.. 1992; RP59500: a proposed mechanism for its bactericidal activity. J Antimicrob Chemother30:9–14[CrossRef]
    [Google Scholar]
  4. Ballow C. H., Amsden G. W.. 1992; Azithromycin: the first azalide antibiotic. Ann Pharmacother26:1253–1261
    [Google Scholar]
  5. Baquero F., Blázquez J.. 1997; Evolution of antibiotic resistance. Trends Ecol Evol12:482–487[CrossRef]
    [Google Scholar]
  6. Bolhuis H., Molenaar D., Poelarends G., Poolman B., Driessen A. J. M., Konings W. N., van Veen H. W.. 1994; Proton motive force-driven and ATP-dependent extrusion systems in multidrug resistant Lactococcus lactis. J Bacteriol176:6957–6964
    [Google Scholar]
  7. Bolhuis H., Poelarends G., Poolman B., Driessen A. J. M., Konings W. N., van Veen H. W.. 1995; The lactococcal lmrP gene encodes a proton motive force-dependent drug transporter. J Biol Chem270:26092–26098[CrossRef]
    [Google Scholar]
  8. Bolhuis H., Brands J. R., Putman M., Poolman B., Driessen A. J. M., Konings W. N., van Veen H. W.. 1996; Energetics and mechanism of drug transport mediated by the lactococcal multidrug transporter LmrP. J Biol Chem271:24123–24128[CrossRef]
    [Google Scholar]
  9. Clancy J., Petitpas J., Dib-Hajj F., Yuan W., Cronan M., Kamath A. V., Bergeron J., Retsema J. A.. 1996; Molecular cloning and functional analysis of a novel macrolide-resistance determinant, mefA , from Streptococcus pyogenes. Mol Microbiol22:867–879[CrossRef]
    [Google Scholar]
  10. Cohen M. L.. 1992; Epidemiology of drug resistance: implications for a post-antimicrobial era. Science257:1050–1054[CrossRef]
    [Google Scholar]
  11. Contreras A., Vásquez D.. 1977; Cooperative and antagonistic interactions of peptidyl-tRNA and antibiotics with bacterial ribosomes. Eur J Biochem74:539–547[CrossRef]
    [Google Scholar]
  12. Davies J.. 1994; Inactivation of antibiotics and the dissemination of resistance genes. Science264:375–381[CrossRef]
    [Google Scholar]
  13. van der Does C., Manting E. H., Kaufmann A., Lutz M., Driessen A. J. M.. 1998; Interaction between SecA and SecYEG in micellar solution and formation of the membrane-inserted state. Biochemistry37:201–210[CrossRef]
    [Google Scholar]
  14. Edgar R., Bibi E.. 1997; MdfA, an Escherichia coli multidrug resistance protein with an extraordinarily broad spectrum of drug recognition. J Bacteriol179:2274–2280
    [Google Scholar]
  15. Gasser F.. 1994; Safety of lactic acid bacteria and their occurrence in human clinical infections. Bull Inst Pasteur92:45–67
    [Google Scholar]
  16. Glaasker E., Konings W. N., Poolman B.. 1996; The application of pH-sensitive fluorescent dyes in lactic acid bacteria reveals distinct extrusion systems for unmodified and conjugated dyes. Mol Membr Biol13:173–181[CrossRef]
    [Google Scholar]
  17. Guffanti A. A., Krulwich T. A.. 1995; Tetracycline/H+ antiport and Na+/H+ antiport catalyzed by the Bacillus subtilis TetA(L)transporter expressed in Escherichia coli. J Bacteriol 177:4557–4561
    [Google Scholar]
  18. Kang L., Rybak M. J.. 1995; Pharmacodynamics of RP59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin cloth model. Antimicrob Agents Chemother39:1505–1511[CrossRef]
    [Google Scholar]
  19. Kuipers O. P., Beerthuyzen M. M., Siezen R. J., de Vos W. M.. 1993; Characterization of the nisin gene cluster nisABTCIPR of Lactococcus lactis : requirement of expression of the nisA and nisI genes for development of immunity. Eur J Biochem216:281–291[CrossRef]
    [Google Scholar]
  20. Leclerq R., Courvalin P.. 1991; Intrinsic and unusual resistance to macrolide, lincosamide, and streptogramin antibiotics in bacteria. Antimicrob Agents Chemother35:1273–1276[CrossRef]
    [Google Scholar]
  21. Levy S. B.. 1998; The challenge of antibiotic resistance. Sci Am278:32–39
    [Google Scholar]
  22. Li X.-Z., Nikaido H., Poole K.. 1995; Role of MexA-MexB-OprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob Agents Chemother39:1948–1953[CrossRef]
    [Google Scholar]
  23. Molenaar D., Bolhuis H., Abee T., Poolman B., Konings W. N.. 1992; The efflux of a fluorescent probe is catalyzed by an ATP-driven extrusion system in Lactococcus lactis. J Bacteriol174:3118–3124
    [Google Scholar]
  24. Morita Y., Kodama K., Shiota S., Mine T., Kataoka A., Mizushima T., Tsuchiya T.. 1998; NorM, a putative multidrug efflux protein, of Vibrio parahaemoliticus and its homolog in Escherichia coli. Antimicrob Agents Chemother42:1778–1782
    [Google Scholar]
  25. Munske G. R., Lindley E. V., Magnuson J. A.. 1984; Streptococcus faecalis proton gradients and tetracycline transport. J Bacteriol158:49–54
    [Google Scholar]
  26. Neyfakh A. A.. 1992; The multidrug efflux transporter of Bacillus subtilis is a structural and functional homolog of the Staphylococcus NorA protein. Antimicrob Agents Chemother36:484–485[CrossRef]
    [Google Scholar]
  27. Nikaido H., Basina M., Nguyen V., Rosenberg E. Y.. 1998; Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those β-lactam antibiotics containing lipophilic side chains. J Bacteriol180:4686–4692
    [Google Scholar]
  28. Paulsen I. T., Brown M. H., Skurray R. A.. 1996; Proton-dependent multidrug efflux systems. Microbiol Rev60:575–608
    [Google Scholar]
  29. Perreten V., Schwarz F., Cresta L., Boeglin M., Dasen G., Teuber M.. 1997; Antibiotic resistance spread in food. Nature389:801–802
    [Google Scholar]
  30. Putman M., Poolman B., Konings W. N., van Veen H. W.. 1999a; Restrictive use of detergents in the functional reconstitution of the secondary multidrug transporter LmrP. Biochemistry38:1002–1008[CrossRef]
    [Google Scholar]
  31. Putman M., Koole L. A., Konings W. N., van Veen H. W.. 1999b; The secondary multidrug transporter LmrP contains multiple drug interaction sites. Biochemistry38:13900–13905[CrossRef]
    [Google Scholar]
  32. Putman M., Konings W. N., van Veen H. W.. 2000; Antibiotic resistance: the era of the drug pump. Mol Microbiol36:772–774
    [Google Scholar]
  33. Ramaswamy K., Harig J. M., Kleinman J. G., Harris M. S., Barry J. A.. 1989; Sodium-proton exchange in human ileal brush-border membrane vesicles. Biochim Biophys Acta981:193–199[CrossRef]
    [Google Scholar]
  34. Saier M. H. Jr, Paulsen I. T., Sliwinski M. K., Pao S. S., Skurray R. A., Nikaido H.. 1998; Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria. FASEB J12:265–274
    [Google Scholar]
  35. Travis J.. 1994; Reviving the antibiotic miracle?. Science264:360–362
    [Google Scholar]
  36. van Veen H. W., Konings W. N.. 1998; The ABC family of multidrug transporters in microorganisms. Biochim Biophys Acta1365:31–36[CrossRef]
    [Google Scholar]
  37. Weisblum B.. 1995; Erythromycin resistance by ribosome modification. Antimicrob Agents Chemother39:577–585[CrossRef]
    [Google Scholar]
  38. Woodward R. B.. 1957; Struktur und Biogenese der Makrolide: eine neue Klasse von Naturstoffen. Angew Chem69:50–58[CrossRef]
    [Google Scholar]
  39. Yamaguchi A., Udagawa T., Sawai T.. 1990; Transport of divalent cations with tetracycline as mediated by the transposon Tn10-encoded tetracycline resistance protein. J Biol Chem265:4809–4813
    [Google Scholar]
  40. Yamaguchi A., Iwasaki-Ohba Y., Ono N., Kaneko-Ohdera M., Sawai T.. 1991; Stoichiometry of metal-tetracycline/H+ antiport mediated by the transposon Tn10-encoded tetracycline resistance protein. FEBS Lett282:415–418[CrossRef]
    [Google Scholar]
  41. Yoshida H., Bogaki M., Nakamura S., Ubukata K., Konno M.. 1990; Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J Bacteriol172:6942–6949
    [Google Scholar]
  42. Zwietering M. H., Jongenburger I., Rombouts F. M., van ’t Riet K.. 1990; Modelling of the bacterial growth curve. Appl Environ Microbiol56:1875–1881
    [Google Scholar]
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