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Growth Phase-Dependent Expression of Drug Exporters in Escherichia coli and Its Contribution to Drug Tolerance

Asuka Kobayashi,^1,2,3 Hidetada Hirakawa,^1,2,3, Takahiro Hirata,^1,2,3 Kunihiko Nishino,^1,2,3 and Akihito Yamaguchi^1,2,3*

Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047,¹ Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871,² CREST, Japan Science and Technology Corporation, Osaka, Japan³

Received 9 February 2006/ Accepted 16 May 2006

Drug exporters contribute to the intrinsic drug resistance in many organisms. Although there are at least 20 exporter genes in Escherichia coli, most of them apparently do not confer drug resistance in complex laboratory media except for the AcrAB, EmrE, and MdfA efflux systems. In this study, we comprehensively investigated the growth phase-dependent expression of drug exporter genes. The expression of acrAB, emrAB, emrD, emrE, emrKY, mdfA, and ydgFE is stable at moderate levels during any growth phase, whereas mdtEF promoter activity greatly increased with cell growth and reached the maximum level at the late stationary phase. The growth phase-dependent increase in mdtEF expression was also observed on quantitative reverse transcription-PCR analysis. As expected from the transporter expression, the stationary-phase cells actually showed MdtEF-dependent tolerance to drugs and toxic dyes. Growth phase-dependent elevation of mdtEF expression was found to be mediated by the stationary-phase factor rpoS and the RpoS-dependent signaling pathway, Hfq, GadY, and GadX. The induction level was decreased by tnaAB deletion, suggesting that indole sensing stimulates this process.

Present address: Department of Microbiology and Molecular Genetics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.

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