Open AccessMutated Response Regulator graR Is Responsible for Phenotypic Conversion of Staphylococcus aureus from Heterogeneous Vancomycin-Intermediate Resistance to Vancomycin-Intermediate Resistance
Author(s) -
Huimin Neoh,
Longzhu Cui,
Hiroko Yuzawa,
Fumihiko Takeuchi,
Miki Matsuo,
Kazumasa Hiramatsu
Publication year - 2008
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00534-07
Subject(s) - vancomycin , daptomycin , staphylococcus aureus , microbiology and biotechnology , phenotype , biology , methicillin resistant staphylococcus aureus , strain (injury) , regulator , drug resistance , genetics , gene , bacteria , anatomy
Multistep genetic alteration is required for methicillin-resistantStaphylococcus aureus (MRSA) to achieve the level of vancomycin resistance of vancomycin-intermediateS. 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-susceptibleS. aureus [VSSA]), we identified a mutation in the response regulator of thegraSR two-component regulatory system. Introduction of mutatedgraR , designatedgraR *, but not intactgraR , designatedgraRn , 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 thatgraR * expression was effective only in the physiological milieu of hetero-VISA cell to achieve a VISA phenotype. Interestingly, the overexpression ofgraR * increased the daptomycin MICs in both Mu3 and N315 and decreased the oxacillin MIC in N315.