This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McAleese, F.
Right arrow Articles by Bradford, P. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McAleese, F.
Right arrow Articles by Bradford, P. A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2005, p. 1865-1871, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1865-1871.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Novel MATE Family Efflux Pump Contributes to the Reduced Susceptibility of Laboratory-Derived Staphylococcus aureus Mutants to Tigecycline

Fionnuala McAleese,1* Peter Petersen,1 Alexey Ruzin,1 Paul M. Dunman,1,{dagger} Ellen Murphy,1 Steven J. Projan,2 and Patricia A. Bradford1

Wyeth Research, Pearl River, New York,1 Cambridge, Massachusetts2

Received 24 August 2004/ Returned for modification 9 October 2004/ Accepted 26 January 2005

Tigecycline, an expanded-broad-spectrum glycylcycline antibiotic is not affected by the classical tetracycline resistance determinants found in Staphylococcus aureus. The in vitro selection of mutants with reduced susceptibility to tigecycline was evaluated for two methicillin-resistant S. aureus strains by serial passage in increasing concentrations of tigecycline. Both strains showed a stepwise elevation in tigecycline MIC over a period of 16 days, resulting in an increase in tigecycline MIC of 16- and 32-fold for N315 and Mu3, respectively. Transcriptional profiling revealed that both mutants exhibited over 100-fold increased expression of a gene cluster, mepRAB (multidrug export protein), encoding a MarR-like transcriptional regulator (mepR), a novel MATE family efflux pump (mepA), and a hypothetical protein of unknown function (mepB). Sequencing of the mepR gene in the mutant strains identified changes that presumably inactivated the MepR protein, which suggested that MepR functions as a repressor of mepA. Overexpression of mepA in a wild-type background caused a decrease in susceptibility to tigecycline and other substrates for MATE-type efflux pumps, although it was not sufficient to confer high-level resistance to tigecycline. Complementation of the mepR defect by overexpressing a wild-type mepR gene reduced mepA transcription and lowered the tigecycline MIC in the mutants. Transcription of tet(M) also increased by over 40-fold in the Mu3 mutant. This was attributed to a deletion in the promoter region of the gene that removed a stem-loop responsible for transcriptional attenuation. However, overexpression of the tet(M) transcript in a tigecycline-susceptible strain was not enough to significantly increase the MIC of tigecycline. These results suggest that the overexpression of mepA but not tet(M) may contribute to decreased susceptibility of tigecycline in S. aureus.

* Corresponding author. Mailing address: Wyeth Research, Room 3219, Bldg. 200, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-2432. Fax: (845) 602-5671. E-mail: mcaleef{at}wyeth.com.

{dagger} Present address: 986495, Department of Microbiology and Pathology, University of Nebraska Medical Center, Omaha, NE 68198.

Antimicrobial Agents and Chemotherapy, May 2005, p. 1865-1871, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1865-1871.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Vaudaux, P., Fleury, B., Gjinovci, A., Huggler, E., Tangomo-Bento, M., Lew, D. P. (2009). Comparison of Tigecycline and Vancomycin for Treatment of Experimental Foreign-Body Infection Due to Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 53: 3150-3152 [Abstract] [Full Text]  
  • Kumaraswami, M., Schuman, J. T., Seo, S. M., Kaatz, G. W., Brennan, R. G. (2009). Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res 37: 1211-1224 [Abstract] [Full Text]  
  • Goff, D. A., Dowzicky, M. J. (2007). Prevalence and regional variation in meticillin-resistant Staphylococcus aureus (MRSA) in the USA and comparative in vitro activity of tigecycline, a glycylcycline antimicrobial. J Med Microbiol 56: 1189-1193 [Abstract] [Full Text]  
  • Chen, J., Novick, R. P. (2007). svrA, a multi-drug exporter, does not control agr. Microbiology 153: 1604-1608 [Abstract] [Full Text]  
  • Anderson, K. L., Roberts, C., Disz, T., Vonstein, V., Hwang, K., Overbeek, R., Olson, P. D., Projan, S. J., Dunman, P. M. (2006). Characterization of the Staphylococcus aureus Heat Shock, Cold Shock, Stringent, and SOS Responses and Their Effects on Log-Phase mRNA Turnover.. J. Bacteriol. 188: 6739-6756 [Abstract] [Full Text]  
  • Morosini, M.-I., Garcia-Castillo, M., Coque, T. M., Valverde, A., Novais, A., Loza, E., Baquero, F., Canton, R. (2006). Antibiotic Coresistance in Extended-Spectrum-{beta}-Lactamase-Producing Enterobacteriaceae and In Vitro Activity of Tigecycline.. Antimicrob. Agents Chemother. 50: 2695-2699 [Abstract] [Full Text]  
  • Kasbekar, N. (2006). Tigecycline: A new glycylcycline antimicrobial agent.. Am J Health Syst Pharm 63: 1235-1243 [Abstract] [Full Text]  
  • Olson, M. W., Ruzin, A., Feyfant, E., Rush, T. S. III, O'Connell, J., Bradford, P. A. (2006). Functional, biophysical, and structural bases for antibacterial activity of tigecycline.. Antimicrob. Agents Chemother. 50: 2156-2166 [Abstract] [Full Text]  
  • Kaatz, G. W., DeMarco, C. E., Seo, S. M. (2006). MepR, a Repressor of the Staphylococcus aureus MATE Family Multidrug Efflux Pump MepA, Is a Substrate-Responsive Regulatory Protein.. Antimicrob. Agents Chemother. 50: 1276-1281 [Abstract] [Full Text]  
  • Senn, M. M., Bischoff, M., von Eiff, C., Berger-Bachi, B. (2005). {sigma}B Activity in a Staphylococcus aureus hemB Mutant. J. Bacteriol. 187: 7397-7406 [Abstract] [Full Text]  
  • Poole, K. (2005). Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 56: 20-51 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»