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J. Biol. Chem., Vol. 279, Issue 10, 9064-9071, March 5, 2004

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A RecA-LexA-dependent Pathway Mediates Ciprofloxacin-induced Fibronectin Binding in Staphylococcus aureus^*

Carmelo Bisognano, William L. Kelley¶, Tristan Estoppey, Patrice Francois, Jacques Schrenzel, Dongmei Li, Daniel P. Lew, David C. Hooper||, Ambrose L. Cheung**, and Pierre Vaudaux

From the Division of Infectious Diseases, University Hospital, CH-1211 Geneva 14, Switzerland, the ^||Infectious Disease Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-2696, and the ^**Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire 03755

Subinhibitory concentrations of ciprofloxacin (CPX) raise the fibronectin-mediated attachment of fluoroquinolone-resistant Staphylococcus aureus by selectively inducing fnbB coding for one of two fibronectin-binding proteins: FnBPB. To identify candidate regulatory pathway(s) linking drug exposure to up-regulation of fnbB, we disrupted the global response regulators agr, sarA, and recA in the highly quinolone-resistant strain RA1. Whereas agr and sarA mutants of RA1 exposed to CPX still displayed increased adhesion to fibronectin, the CPX-triggered response was abolished in the uvs-568 recA mutant, but was restored following complementation with wild type recA. Steady-state levels of recA and fnbB, but not fnbA, mRNA were co-coordinately increased >3-fold in CPX-exposed strain RA1. Electrophoretic mobility shift assays revealed specific binding of purified S. aureus SOS-repressor LexA to recA and fnbB, but not to fnbA or rpoB promoters. DNase I footprint analysis showed LexA binding overlapping the core promoter elements in fnbB. We conclude that activation of recA and derepression of lexA-regulated genes by CPX may represent a response to drug-induced damage that results in a novel induction of a virulence factor leading to increased bacterial tissue adherence.

Received for publication, September 4, 2003 , and in revised form, December 19, 2003.

^* This work was supported by the Swiss National Foundation Grants 32-63710.00 (to P. V.) and 632-57950.99 (to J. S.), and National Institutes of Health Grants AI23988 (to D. C. H.) and AI47441 (to A. L. C.). 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.

Both authors contributed equally to this work.

^¶ To whom correspondence should be addressed. Tel.: 41-22-37-29-819; Fax: 41-22-37-29-830; E-mail: william.kelley{at}hcuge.ch.

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