AAC Accepts, published online ahead of print on 14 May 2007

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meehl, M. Articles by Cheung, A. Search for Related Content PubMed PubMed Citation Articles by Meehl, M. Articles by Cheung, A.

 Previous Article  |  Next Article 

Antimicrob. Agents Chemother. doi:10.1128/AAC.00209-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Interaction of the GraRS Two-Component System with the VraFG ABC-Transporter to Support Vancomycin-Intermediate Resistance in Staphylococcus aureus

Michael Meehl, Silvia Herbert, Friedrich Götz, and Ambrose Cheung^*

Department of Microbiology, Dartmouth Medical School, Hanover, NH, USA; Microbial Genetics, University of Tübingen, Tübingen, Germany

^* To whom correspondence should be addressed. Email: Ambrose.Cheung{at}Dartmouth.edu.

Current treatment for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) relies heavily upon the glycopeptide antibiotic vancomycin. Unfortunately, this practice has led to an intermediate resistance phenotype that is particularly difficult to treat in invasive staphylococcal diseases, such as septicemia and its metastatic complications, including endocarditis. Although the vancomycin intermediate resistance phenotype has been linked to abnormal cell wall structures and autolytic rates, the corresponding genetic changes have not been fully elucidated. Previously, whole-genome array studies listed numerous genes to be over-expressed in vancomycin intermediate sensitive strains including graRS (sacol0716-0717), encoding a two-component regulatory system, as well as the adjacent vraFG (sacol0718-0720), encoding an ATP-binding cassette (ABC) transporter; but the exact contribution of these genes to increased vancomycin resistance has not been defined. In this study, we showed that isogenic strains with mutations in genes encoding the GraRS TCRS and the VraFG ABC-transporter are hypersensitive to vancomycin as well as polymyxin B. Moreover, GraRS regulates the expression of the adjacent VraFG pump, reminiscent of Gram-positive bacteriocin-immunity regulons. Mutations of graRS and vraFG also led to increased autolytic rates and a more negative net surface charge, which may explain, in part, to their increased sensitivity to cationic antimicrobial peptides. Taken together, these data reveal an important genetic mediator to the VISA phenotype and may hold clues to the selective pressures on staphylococci upon exposure to selective cationic peptide antibiotics used in clinical practice.

This article has been cited by other articles:

• Donegan, N. P., Cheung, A. L. (2009). Regulation of the mazEF Toxin-Antitoxin Module in Staphylococcus aureus and Its Impact on sigB Expression. J. Bacteriol. 191: 2795-2805 [Abstract] [Full Text]  
• Renzoni, A., Kelley, W. L., Barras, C., Monod, A., Huggler, E., Francois, P., Schrenzel, J., Studer, R., Vaudaux, P., Lew, D. P. (2009). Identification by Genomic and Genetic Analysis of Two New Genes Playing a Key Role in Intermediate Glycopeptide Resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 53: 903-911 [Abstract] [Full Text]  
• Cui, L., Neoh, H.-m., Shoji, M., Hiramatsu, K. (2009). Contribution of vraSR and graSR Point Mutations to Vancomycin Resistance in Vancomycin-Intermediate Staphylococcus aureus. Antimicrob. Agents Chemother. 53: 1231-1234 [Abstract] [Full Text]  
• Howden, B. P., Stinear, T. P., Allen, D. L., Johnson, P. D. R., Ward, P. B., Davies, J. K. (2008). Genomic Analysis Reveals a Point Mutation in the Two-Component Sensor Gene graS That Leads to Intermediate Vancomycin Resistance in Clinical Staphylococcus aureus. Antimicrob. Agents Chemother. 52: 3755-3762 [Abstract] [Full Text]  
• Shanks, R. M. Q., Meehl, M. A., Brothers, K. M., Martinez, R. M., Donegan, N. P., Graber, M. L., Cheung, A. L., O'Toole, G. A. (2008). Genetic Evidence for an Alternative Citrate-Dependent Biofilm Formation Pathway in Staphylococcus aureus That Is Dependent on Fibronectin Binding Proteins and the GraRS Two-Component Regulatory System. Infect. Immun. 76: 2469-2477 [Abstract] [Full Text]  
• Stauff, D. L., Bagaley, D., Torres, V. J., Joyce, R., Anderson, K. L., Kuechenmeister, L., Dunman, P. M., Skaar, E. P. (2008). Staphylococcus aureus HrtA Is an ATPase Required for Protection against Heme Toxicity and Prevention of a Transcriptional Heme Stress Response. J. Bacteriol. 190: 3588-3596 [Abstract] [Full Text]