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Antimicrobial Agents and Chemotherapy, March 2004, p. 909-917, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.909-917.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Novel Chromosomally Encoded Multidrug Efflux Transporter MdeA in Staphylococcus aureus

Jianzhong Huang,* Paul W. O'Toole,{dagger} Wei Shen, Heather Amrine-Madsen, Xinhe Jiang, Neethan Lobo, Leslie M. Palmer, LeRoy Voelker, Frank Fan,{ddagger} Michael N. Gwynn, and Damien McDevitt

Department of Microbiology, Microbial Musculoskeletal and Proliferative Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline, Collegeville, Pennsylvania 19426

Received 20 May 2003/ Returned for modification 13 August 2003/ Accepted 12 November 2003

Antibiotic efflux is an important mechanism of resistance in pathogenic bacteria. Here we describe the identification and characterization of a novel chromosomally encoded multidrug resistance efflux protein in Staphylococcus aureus, MdeA (multidrug efflux A). MdeA was identified from screening an S. aureus open reading frame expression library for resistance to antibiotic compounds. When overexpressed, MdeA confers resistance on S. aureus to a range of quaternary ammonium compounds and antibiotics, but not fluoroquinolones. MdeA is a 52-kDa protein with 14 predicted transmembrane segments. It belongs to the major facilitator superfamily and is most closely related, among known efflux proteins, to LmrB of Bacillus subtilis and EmrB of Escherichia coli. Overexpression of mdeA in S. aureus reduced ethidium bromide uptake and enhanced its efflux, which could be inhibited by reserpine and abolished by an uncoupler. The mdeA promoter was identified by primer extension. Spontaneous mutants selected for increased resistance to an MdeA substrate had undergone mutations in the promoter for mdeA, and their mdeA transcription levels were increased by as much as 15-fold. The mdeA gene was present in the genomes of all six strains of S. aureus examined. Uncharacterized homologs of MdeA were present elsewhere in the S. aureus genome, but their overexpression did not mediate resistance to the antibacterials tested. However, MdeA homologs were identified in other bacteria, including Bacillus anthracis, some of which were shown to be functional orthologs of MdeA.

* Corresponding author. Mailing address: Microbiology Dept., GlaxoSmithKline, UP-1345, 1250 S. Collegeville Rd., Collegeville, PA 19426-0989. Phone: (610) 917-6908. Fax: (610) 917-7901. E-mail: Jianzhong.Huang-1{at}gsk.com.

{dagger} Present address: Department of Microbiology, University College Cork, Cork, Ireland.

{ddagger} Present address: Promega R&D, Madison WI 53711.

Antimicrobial Agents and Chemotherapy, March 2004, p. 909-917, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.909-917.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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