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JAC Advance Access published online on November 4, 2009
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkp394
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Genetic changes associated with glycopeptide resistance in Staphylococcus aureus: predominance of amino acid substitutions in YvqF/VraSR

Yoshihisa Kato*, Takahisa Suzuki, Takashi Ida and Kazunori Maebashi

Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan

Received 25 June 2009; returned 21 August 2009; revised 28 September 2009; accepted 8 October 2009

* Corresponding author. Tel: +81-45-541-2521; Fax: +81-45-545-3152; E-mail: yoshihisa_kato{at}meiji.co.jp

Objectives: To further understand the mechanism of intermediate-level glycopeptide resistance, resulting from multiple endogenous mutations, in both laboratory-derived and clinically isolated Staphylococcus aureus.

Methods: Laboratory-derived S. aureus strains were generated under selection using a variety of cell-wall-active antibiotics. Complete sequences of 27 genes, including 17 two-component histidine kinase sensors, were then compared with those of their susceptible parent strain. Further genetic analysis was performed on 125 clinical S. aureus isolates and 42 geographically diverse isolates of vancomycin-intermediate S. aureus (VISA).

Results: Selective pressure using imipenem resulted in single point mutations leading to amino acid substitutions in two genes: vraS, encoding a two-component histidine kinase sensor; and SA1702 (also called yvqF, located immediately upstream of vraS), encoding a conserved hypothetical protein. The accumulation of the mutation in two distinct proteins—MsrR, a peptide methionine sulphoxide reductase regulator, and TcaA, a teicoplanin-resistance-associated protein—correlated with further increases in the glycopeptide MIC. The prevalence of YvqF/VraSR mutants among 125 clinical isolates along with the corresponding teicoplanin MICs was as follows: 0% (0/39), ≤1 mg/L; 48.6% (17/35), 2 mg/L; 72.7% (24/33), 4 mg/L; 93.8% (15/16), 8 mg/L; and 100% (2/2), 16 mg/L. Genetic analysis of 42 VISA isolates also identified the predominant amino acid substitutions in YvqF/VraS: 9 isolates (21.4%) revealed mutations in YvqF, followed by 7 isolates with mutations in VraS (16.7%).

Conclusions: Our findings provide novel insights into the high prevalence and genetic diversity of YvqF/VraSR mutants among clinical S. aureus isolates with reduced susceptibility to teicoplanin.

Key Words: vancomycin , teicoplanin , two-component regulatory systems


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