This Article Full Text (PDF) Other Versions of this Article: JB.01045-07v1 189/24/9066    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nishino, K. Articles by Yamaguchi, A. Search for Related Content PubMed PubMed Citation Articles by Nishino, K. Articles by Yamaguchi, A.

 Previous Article  |  Next Article 

J. Bacteriol. doi:10.1128/JB.01045-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulation of multidrug efflux systems involved in multidrug and metal resistance of Salmonella enterica serovar Typhimurium

Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, PRESTO and CREST, Japan Science and Technology Corporation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

^* To whom correspondence should be addressed. Email: akihito{at}sanken.osaka-u.ac.jp.

	Abstract

Multidrug-resistant strains of Salmonella are now encountered frequently and the rates of multidrug resistance have increased considerably in recent years. Here, we report that the two-component regulatory system BaeSR increases multidrug and metal resistance in Salmonella through induction of drug efflux systems. Screening of random fragments of genomic DNA for ability to increase -lactam resistance in Salmonella enterica led to the isolation of a plasmid containing baeR, which codes for the response regulator of BaeSR. When over-expressed, baeR significantly increased the resistance of the acrB strain to oxacillin, cloxacillin and nafcillin. baeR over-expression conferred resistance to novobiocin and deoxycholate as well as -lactams in Salmonella. The increase in drug resistance caused by baeR over-expression was completely suppressed by deletion of the multifunctional outer membrane channel gene tolC. TolC interacts with different drug efflux systems. Among the nine drug efflux systems in Salmonella, quantitative real-time PCR analysis showed that BaeR induced the expression of acrD and mdtABC. Double deletion of these two genes completely suppressed BaeR-mediated multidrug resistance, whereas single deletion of either gene did not. The promoter regions of acrD and mdtABC harbor binding sites for the response regulator BaeR, which activates acrD and mdtABC transcription in response to indole, copper and zinc. In addition to their role in multidrug resistance, we found that BaeSR, AcrD and MdtABC contribute to copper and zinc resistance in Salmonella. Our results indicate that the BaeSR system increases multidrug and metal resistance in Salmonella by inducing the AcrD and MdtABC drug efflux systems. We found previously uncharacterized physiological role for the AcrD and MdtABC multidrug efflux systems in metal resistance.