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Antimicrobial Agents and Chemotherapy, January 2008, p. 45-53, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00534-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mutated Response Regulator graR Is Responsible for Phenotypic Conversion of Staphylococcus aureus from Heterogeneous Vancomycin-Intermediate Resistance to Vancomycin-Intermediate Resistance{triangledown}

Hui-min Neoh,1 Longzhu Cui,1,2 Harumi Yuzawa,1 Fumihiko Takeuchi,2 Miki Matsuo,1 and Keiichi Hiramatsu1,2*

Department of Bacteriology,1 Department of Infection Control Science, Faculty of Medicine, Juntendo University, 2-1-1 Bunkyo-Ku, Tokyo, Japan 113-84212

Received 23 April 2007/ Returned for modification 7 May 2007/ Accepted 9 October 2007

Multistep genetic alteration is required for methicillin-resistant Staphylococcus aureus (MRSA) to achieve the level of vancomycin resistance of vancomycin-intermediate S. aureus (VISA). In the progression of vancomycin resistance, strains with heterogeneous vancomycin resistance, designated hetero-VISA, are observed. In studying the whole-genome sequencing of the representative hetero-VISA strain Mu3 and comparing it with that of closely related MRSA strains Mu50 (VISA) and N315 (vancomycin-susceptible S. aureus [VSSA]), we identified a mutation in the response regulator of the graSR two-component regulatory system. Introduction of mutated graR, designated graR*, but not intact graR, designated graRn, could convert the hetero-VISA phenotype of Mu3 into a VISA phenotype which was comparable to that of Mu50. The same procedure did not appreciably increase the vancomycin resistance of VSSA strain N315, indicating that graR* expression was effective only in the physiological milieu of hetero-VISA cell to achieve a VISA phenotype. Interestingly, the overexpression of graR* increased the daptomycin MICs in both Mu3 and N315 and decreased the oxacillin MIC in N315.

* Corresponding author. Mailing address: Department of Bacteriology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, Japan 113-8421. Phone: (813) 3-5802-1040. Fax: (813) 3-5684-7830. E-mail: khiram06{at}med.juntendo.ac.jp

{triangledown} Published ahead of print on 22 October 2007.

Antimicrobial Agents and Chemotherapy, January 2008, p. 45-53, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00534-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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