AcrAB Multidrug Efflux Pump Regulation in Salmonella enterica serovar Typhimurium by RamA in Response to Environmental Signals

• Published in: The Journal of biological chemistry Vol. 283; no. 35; pp. 24245 - 24253
• Main Authors: Nikaido, Eiji, Yamaguchi, Akihito, Nishino, Kunihiko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.08.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Bacterial Proteins - biosynthesis; Bacterial Proteins - genetics; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cholic Acid - pharmacology; Drug Resistance, Multiple, Bacterial - drug effects; Drug Resistance, Multiple, Bacterial - physiology; Escherichia coli; Gene Expression Regulation, Bacterial - drug effects; Gene Expression Regulation, Bacterial - physiology; Indoles - metabolism; Indoles - pharmacology; Membrane Transport Proteins; Membrane Transport, Structure, Function, and Biogenesis; Multidrug Resistance-Associated Proteins - biosynthesis; Multidrug Resistance-Associated Proteins - genetics; Salmonella enterica; Salmonella typhimurium - genetics; Salmonella typhimurium - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Trans-Activators - biosynthesis; Trans-Activators - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M804544200

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.