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Antimicrobial Agents and Chemotherapy, October 2006, p. 3424-3434, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00356-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of VraSR in Antibiotic Resistance and Antibiotic-Induced Stress Response in Staphylococcus aureus

S. Gardete,1,2 S. W. Wu,2 S. Gill,3 and A. Tomasz2*

Molecular Genetics Laboratory, Instituto de Tecnologia Química e Biológica da Universidade Nova de Lisboa, 2780 Oeiras, Portugal,1 Laboratory of Microbiology, The Rockefeller University, 1230 York Avenue, New York, New York 10021,2 The Institute for Genomic Research, 9712 Medical Centre Drive, Rockville, Maryland 208503

Received 23 March 2006/ Returned for modification 24 June 2006/ Accepted 14 July 2006

Exposure of Staphylococcus aureus to cell wall inhibitors induces massive overexpression of a number of genes, provided that the VraSR two-component sensory regulatory system is intact. Inactivation of vraS blocks this transcriptional response and also causes a drastic reduction in the levels of resistance to beta-lactam antibiotics and vancomycin. We used an experimental system in which the essential cell wall synthesis gene of S. aureus, pbpB, was put under the control of an isopropyl-ß-D-thiogalactopyranoside-inducible promoter in order to induce reversible perturbations in cell wall synthesis without the use of any cell wall-active inhibitor. Changes in the level of transcription of pbpB were rapidly followed by parallel changes in the vraSR signal, and the abundance of the pbpB transcript was precisely mirrored by the abundance of the transcripts of vraSR and some additional genes that belong to the VraSR regulon. Beta-lactam resistance in S. aureus appears to involve a complex stress response in which VraSR performs the critical role of a sentinel system capable of sensing the perturbation of cell wall synthesis and allowing mobilization of genes that are essential for the generation of a highly resistant phenotype. One of the sites in cell wall synthesis "sensed" by the VraSR system appears to be a step catalyzed by PBP 2.

* Corresponding author. Mailing address: The Rockefeller University, Laboratory of Microbiology, 1230 York Avenue, New York, NY 10021. Phone: (212) 327-8278. Fax: (212) 327-8688. E-mail: tomasz{at}mail.rockefeller.edu.

Antimicrobial Agents and Chemotherapy, October 2006, p. 3424-3434, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00356-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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