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JAC Advance Access published online on September 1, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg406
© 2003 by The British Society for Antimicrobial Chemotherapy
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© 2003 The British Society for Antimicrobial Chemotherapy

Original article

{beta}-Lactam resistance modulated by the overexpression of response regulators of two-component signal transduction systems in Escherichia coli

Hidetada Hirakawa 1 , Kunihiko Nishino 1 , Junko Yamada 1 , Takahiro Hirata 1 , and Akihito Yamaguchi 1 *

1 Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047; Faculty of Pharmaceutical Science, Osaka University, Suita, Osaka 565-0871; CREST, Japan Science and Technology Corporation, Osaka 567-0047, Japan

* Corresponding author. E-mail: akihito{at}sanken.osaka-u.ac.jp.

Received 27 March 2003 ; revised 4 July 2003 ; accepted 9 July 2003

Abstract

Objectives: In Escherichia coli, there are 32 open reading frames assumed, on the basis of sequence similarities, to be response regulator genes of two-component signal transduction systems. We cloned all 32 response regulators and examined whether or not response regulator-overexpressing cells confer resistance to {beta}-lactam antibiotics in E. coli.

Methods: E. coli KAM3 (acrB), a drug-hypersusceptible mutant, was used as a host strain for the overproduction of response regulators. MICs were determined by the agar dilution method.

Results: Thirteen response regulators out of 32 genes, namely baeR, cheY, cpxR, creB, evgA, fimZ, narL, ompR, rcsB, rstA, yedW, yehT and dcuR, conferred increased {beta}-lactam resistance. Among them, overexpression of baeR, evgA, rcsB and dcuR conferred high-level resistance. The baeR- and evgA-mediated resistance is due to up-regulation of the expression of multidrug exporter genes, acrD and mdtABC for baeR, and yhiUV for evgA, because baeR- and evgA-mediated resistance was completely absent in strains lacking these exporter genes. The fimZ-mediated cefalothin resistance is due to the chromosomal ampC gene, because the ampC deletion strain did not show fimZ-mediated resistance.

Conclusions: Two-component signal transduction systems contribute to {beta}-lactam resistance in E. coli. Multidrug exporters play roles in two-component signal transduction system-mediated {beta}-lactam resistance.

Keywords: {beta}-lactams, multidrug exporters, drug resistance, E. coli
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