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Antimicrobial Agents and Chemotherapy, May 2005, p. 1857-1864, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1857-1864.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Multidrug Resistance in Staphylococcus aureus Due to Overexpression of a Novel Multidrug and Toxin Extrusion (MATE) Transport Protein

Glenn W. Kaatz,1,2* Fionnuala McAleese,3 and Susan M. Seo2

The John D. Dingell Department of Veteran's Affairs Medical Center,1 The Department of Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan,2 Wyeth Research, Pearl River, New York3

Received 24 August 2004/ Returned for modification 9 October 2004/ Accepted 23 January 2005

Efflux is an important mechanism of multidrug resistance (MDR) in bacteria. The multidrug and toxin extrusion (MATE) family is the most recently described group of MDR efflux proteins, none of which have previously been identified in Staphylococcus aureus. Two independently derived S. aureus mutants having efflux-related MDR phenotypes were studied using microarray technology and a marked overexpression of an open reading frame (ORF; mepA) encoding a protein homologous with MATE family proteins was observed in both. There was concomitant overexpression of ORFs in close proximity to mepA (~100 bp) encoding a MarR-type regulator (mepR, upstream of mepA) and a protein of unknown function (mepB, downstream). Experiments in which mepA was overexpressed or disrupted revealed that the encoded protein has a broad substrate profile that includes several monovalent and divalent biocides and the fluoroquinolone antimicrobial agents norfloxacin and ciprofloxacin. The function of MepB is obscure, it does not contribute to the MDR phenotype conferred by MepA. MepR overexpression reversed the MDR phenotypes of both mutants by repressing mepA transcription. All three ORFs are preferentially transcribed as a single mepRAB unit, suggesting that the three genes form an operon.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, B4333 John D. Dingell VA Medical Center, 4646 John R, Detroit, MI 48201. Phone: (313) 576-4491. Fax: (313) 576-1112. E-mail: gkaatz{at}juno.com.

Antimicrobial Agents and Chemotherapy, May 2005, p. 1857-1864, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1857-1864.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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