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Antimicrobial Agents and Chemotherapy, April 2004, p. 1320-1328, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1320-1328.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Enhancement of the mexAB-oprM Efflux Pump Expression by a Quorum-Sensing Autoinducer and Its Cancellation by a Regulator, MexT, of the mexEF-oprN Efflux Pump Operon in Pseudomonas aeruginosa

Hideaki Maseda,1* Isao Sawada,2 Kohjiro Saito,1 Hiroo Uchiyama,2 Taiji Nakae,1 and Nobuhiko Nomura2*

Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8572,2 Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan1

Received 16 May 2003/ Returned for modification 9 August 2003/ Accepted 14 December 2003

nfxC-type cells of Pseudomonas aeruginosa that produce the MexEF-OprN efflux pump exhibit resistance to fluoroquinolones and chloramphenicol and hypersusceptibility to most classical ß-lactam antibiotics. We investigated the molecular mechanism of how the nfxC mutation causes ß-lactam hypersusceptibility. The MexAB-OprM extrusion pump transports and confers resistance to ß-lactam antibiotics. Interestingly, expression of the mexAB-oprM operon reached the highest level during the mid-stationary growth phase in both wild-type and nfxC-type mutant strains, suggesting that expression of the mexAB-oprM operon may be controlled by cell density-dependent regulation such as quorum sensing. This assumption was verified by demonstrating that exogenous addition of the quorum-sensing autoinducer N-butyryl-L-homoserine lactone (C4-HSL) enhanced the expression of MexAB-OprM, whereas N-(3-oxododecanoyl)-L-homoserine lactone had only a slight effect. Furthermore, this C4-HSL-mediated enhancement of mexAB-oprM expression was repressed by MexT, a positive regulator of the mexEF-oprN operon. It was concluded that ß-lactam hypersusceptibility in nfxC-type mutant cells is caused by MexT-mediated cancellation of C4-HSL-mediated enhancement of MexAB-OprM expression.

* Corresponding authors. Mailing address for Hideaki Maseda: Gene Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan. Phone: 81-298-53-7792. Fax: 81-298-53-7723. E-mail: maseda{at}sakura.cc.tsukuba.ac.jp. Mailing address for Nobuhiko Nomura: Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan. Phone: 81-298-53-6627. Fax: 81-298-53-6627. E-mail: nomunobu{at}sakura.cc.tsukuba.ac.jp.

Antimicrobial Agents and Chemotherapy, April 2004, p. 1320-1328, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1320-1328.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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