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. 1996 Oct;40(10):2288–2290. doi: 10.1128/aac.40.10.2288

Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa.

T Köhler 1, M Kok 1, M Michea-Hamzehpour 1, P Plesiat 1, N Gotoh 1, T Nishino 1, L K Curty 1, J C Pechere 1
PMCID: PMC163521  PMID: 9036831

Abstract

Pseudomonas aeruginosa possesses at least two multiple drug efflux systems which are defined by the outer membrane proteins OprM and OprJ. We have found that mutants overexpressing OprM were two- and eightfold more resistant than their wild-type parent to sulfamethoxazole (SMX) and trimethoprim (TMP), respectively. For OprJ-overproducing strains, MICs of TMP increased fourfold but those of SMX were unchanged. Strains overexpressing OprM, but not those overexpressing OprJ, became hypersusceptible to TMP and SMX when oprM was inactivated. The wild-type antibiotic profile could be restored in an oprM mutant by transcomplementation with the cloned oprM gene. These results demonstrate that the mexABoprM multidrug efflux system is mainly responsible for the intrinsic resistance of P. aeruginosa to TMP and SMX.

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Selected References

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  1. Baccanari D. P., Joyner S. S. Dihydrofolate reductase hysteresis and its effect of inhibitor binding analyses. Biochemistry. 1981 Mar 31;20(7):1710–1716. doi: 10.1021/bi00510a002. [DOI] [PubMed] [Google Scholar]
  2. Bryson V., Szybalski W. Microbial Selection. Science. 1952 Jul 18;116(3003):45–51. doi: 10.1126/science.116.3003.45. [DOI] [PubMed] [Google Scholar]
  3. Burns J. L., Wadsworth C. D., Barry J. J., Goodall C. P. Nucleotide sequence analysis of a gene from Burkholderia (Pseudomonas) cepacia encoding an outer membrane lipoprotein involved in multiple antibiotic resistance. Antimicrob Agents Chemother. 1996 Feb;40(2):307–313. doi: 10.1128/aac.40.2.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cohen S. P., McMurry L. M., Hooper D. C., Wolfson J. S., Levy S. B. Cross-resistance to fluoroquinolones in multiple-antibiotic-resistant (Mar) Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction. Antimicrob Agents Chemother. 1989 Aug;33(8):1318–1325. doi: 10.1128/aac.33.8.1318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Friedman A. M., Long S. R., Brown S. E., Buikema W. J., Ausubel F. M. Construction of a broad host range cosmid cloning vector and its use in the genetic analysis of Rhizobium mutants. Gene. 1982 Jun;18(3):289–296. doi: 10.1016/0378-1119(82)90167-6. [DOI] [PubMed] [Google Scholar]
  6. George A. M., Hall R. M., Stokes H. W. Multidrug resistance in Klebsiella pneumoniae: a novel gene, ramA, confers a multidrug resistance phenotype in Escherichia coli. Microbiology. 1995 Aug;141(Pt 8):1909–1920. doi: 10.1099/13500872-141-8-1909. [DOI] [PubMed] [Google Scholar]
  7. Gotoh N., Itoh N., Tsujimoto H., Yamagishi J., Oyamada Y., Nishino T. Isolation of OprM-deficient mutants of Pseudomonas aeruginosa by transposon insertion mutagenesis: evidence of involvement in multiple antibiotic resistance. FEMS Microbiol Lett. 1994 Oct 1;122(3):267–273. doi: 10.1111/j.1574-6968.1994.tb07179.x. [DOI] [PubMed] [Google Scholar]
  8. Hamzehpour M. M., Pechere J. C., Plesiat P., Köhler T. OprK and OprM define two genetically distinct multidrug efflux systems in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1995 Nov;39(11):2392–2396. doi: 10.1128/aac.39.11.2392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Huovinen P., Sundström L., Swedberg G., Sköld O. Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother. 1995 Feb;39(2):279–289. doi: 10.1128/aac.39.2.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Levy S. B. Active efflux mechanisms for antimicrobial resistance. Antimicrob Agents Chemother. 1992 Apr;36(4):695–703. doi: 10.1128/aac.36.4.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Li X. Z., Livermore D. M., Nikaido H. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob Agents Chemother. 1994 Aug;38(8):1732–1741. doi: 10.1128/aac.38.8.1732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Li X. Z., Nikaido H., Poole K. Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1995 Sep;39(9):1948–1953. doi: 10.1128/aac.39.9.1948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ma D., Cook D. N., Hearst J. E., Nikaido H. Efflux pumps and drug resistance in gram-negative bacteria. Trends Microbiol. 1994 Dec;2(12):489–493. doi: 10.1016/0966-842x(94)90654-8. [DOI] [PubMed] [Google Scholar]
  14. Masuda N., Ohya S. Cross-resistance to meropenem, cephems, and quinolones in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1992 Sep;36(9):1847–1851. doi: 10.1128/aac.36.9.1847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Masuda N., Sakagawa E., Ohya S. Outer membrane proteins responsible for multiple drug resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1995 Mar;39(3):645–649. doi: 10.1128/AAC.39.3.645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Morales V. M., Bäckman A., Bagdasarian M. A series of wide-host-range low-copy-number vectors that allow direct screening for recombinants. Gene. 1991 Jan 2;97(1):39–47. doi: 10.1016/0378-1119(91)90007-x. [DOI] [PubMed] [Google Scholar]
  17. Morshed S. R., Lei Y., Yoneyama H., Nakae T. Expression of genes associated with antibiotic extrusion in Pseudomonas aeruginosa. Biochem Biophys Res Commun. 1995 May 16;210(2):356–362. doi: 10.1006/bbrc.1995.1669. [DOI] [PubMed] [Google Scholar]
  18. Nikaido H. Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science. 1994 Apr 15;264(5157):382–388. doi: 10.1126/science.8153625. [DOI] [PubMed] [Google Scholar]
  19. Okusu H., Ma D., Nikaido H. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. J Bacteriol. 1996 Jan;178(1):306–308. doi: 10.1128/jb.178.1.306-308.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Poole K., Krebes K., McNally C., Neshat S. Multiple antibiotic resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux operon. J Bacteriol. 1993 Nov;175(22):7363–7372. doi: 10.1128/jb.175.22.7363-7372.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Poole K., Neshat S., Heinrichs D. Pyoverdine-mediated iron transport in Pseudomonas aeruginosa: involvement of a high-molecular-mass outer membrane protein. FEMS Microbiol Lett. 1991 Feb;62(1):1–5. [PubMed] [Google Scholar]
  22. Visca P., Ciervo A., Orsi N. Cloning and nucleotide sequence of the pvdA gene encoding the pyoverdin biosynthetic enzyme L-ornithine N5-oxygenase in Pseudomonas aeruginosa. J Bacteriol. 1994 Feb;176(4):1128–1140. doi: 10.1128/jb.176.4.1128-1140.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]

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