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Journal of Bacteriology (1)
The Journal of Biological Chemistry (1)
Nikaido, Eiji (2)
Nishino, Kunihiko (2)
Yamaguchi, Akihito (2)
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AcrAB Multidrug Efflux Pump Regulation in Salmonella enterica serovar Typhimurium by RamA in Response to Environmental Signals*
The Journal of Biological Chemistry
Salmonella enterica serovar Typhimurium has at least nine multidrug efflux pumps. Among these pumps, AcrAB is effective in generating drug resistance and has wide substrate specificity. Here we report that indole, bile, and an Escherichia coli conditioned medium induced the AcrAB pump in Salmonella through a specific regulator, RamA. The RamA-binding sites were located in the upstream regions of acrAB and tolC. RamA was required for indole induction of acrAB. Other regulators of acrAB such as MarA, SoxS, Rob, SdiA, and AcrR did not contribute to acrAB induction by indole in Salmonella. Indole activated ramA transcription, and overproduction of RamA caused increased acrAB expression. In contrast, induction of ramA was not required for induction of acrAB by bile. Cholic acid binds to RamA, and we suggest that bile acts by altering pre-existing RamA. This points to two different AcrAB regulatory modes through RamA. Our results suggest that RamA controls the Salmonella AcrAB-TolC multidrug efflux system through dual regulatory modes in response to environmental signals.
Regulation of Multidrug Efflux Systems Involved in Multidrug and Metal Resistance of Salmonella enterica Serovar Typhimurium▿
Journal of Bacteriology
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 the induction of drug efflux systems. Screening of random fragments of genomic DNA for the ability to increase β-lactam resistance in Salmonella enterica led to the isolation of a plasmid containing baeR, which codes for the response regulator of BaeSR. When overexpressed, baeR significantly increased the resistance of the ΔacrB strain to oxacillin, cloxacillin, and nafcillin. baeR overexpression conferred resistance to novobiocin and deoxycholate, as well as to β-lactams in Salmonella. The increase in drug resistance caused by baeR overexpression 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 a previously uncharacterized physiological role for the AcrD and MdtABC multidrug efflux systems in metal resistance.
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