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Antimicrob. Agents Chemother. doi:10.1128/AAC.00722-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Functional characterization of TcaA: minimal requirement for teicoplanin susceptibility and role in Caenorhabditis elegans virulence

Institute of Medical Microbiology, University of Zurich, Gloriastr. 32, 8006 Zurich, Switzerland, Division of Infectious Diseases and International Health, University of Virginia Health System, P.O. Box 801361, Charlottesville, Virginia 22908, USA

^* To whom correspondence should be addressed. Email: mccallum{at}immv.uzh.ch.

	Abstract

Inactivation of TcaA contributes to intrinsic teicoplanin resistance in experimental and clinical isolates of glycopeptide intermediate resistant Staphylococcus aureus (GISA). PhoA fusions confirmed that TcaA is a transmembrane protein with a short intracellular N-terminal domain containing a C4-zinc finger binding motif, a single membrane spanning domain and a large extracellular C-terminal domain. The region conferring teicoplanin susceptibility was narrowed down to the transmembrane part and the first third of the extracellular domain of TcaA, suggesting that neither the C4-zinc finger binding motif nor the C-terminus contributed to teicoplanin susceptibility. TcaA belongs to the cell wall-stress stimulon, which comprises a set of genes universally upregulated by cell wall damage. Induction of tcaA was shown to be fully dependent on the two-component regulatory system VraSR. A 66-bp region upstream of the transcriptional start site, containing an inverted repeat partially covering the promoter box, was shown to be essential for VraSR mediated induction by cell wall stress. Interestingly, induction or overexpression of tcaA did not contribute further to teicoplanin susceptibility, suggesting that small amounts of TcaA, such as those present under normal uninduced conditions, were sufficient for TcaA-mediated teicoplanin susceptibility. The strong attenuation of tcaA deletion mutants in a Caenorhabditis elegans survival assay suggested that TcaA may, in addition to affecting glycopeptide susceptibility, also play a role in virulence.