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J. Biol. Chem., Vol. 283, Issue 35, 24245-24253, August 29, 2008

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

Eiji Nikaido¹, Akihito Yamaguchi², and Kunihiko Nishino^¶3

From the Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, and Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 567-0047 and ^¶PRESTO, Japan Science and Technology Corporation, Tokyo 102-0075, Japan

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.

Received for publication, June 13, 2008

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^* This work was supported in part by Takeda Science Foundation, Inamori Foundation, the PRESTO program of the Japan Science and Technology Agency (to K. N.), the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, and by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Japan Society for the Promotion of Science (to A. Y. and K. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a research fellowship from the Japan Society for the Promotion of Science for Young Scientists.

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² To whom correspondence may be addressed. Tel.: 81-6-6879-8545; Fax: 81-6-6879-8549; E-mail: akihito{at}sanken.osaka-u.ac.jp.

³ To whom correspondence may be addressed. Tel.: 81-6-6879-8546; Fax: 81-6-6879-8549; E-mail: nishino{at}sanken.osaka-u.ac.jp.

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