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Heterogeneous vancomycin-intermediate  Staphylococcus aureus  (hVISA) is associated with clinical treatment failure. However, the resistance mechanism of hVISA has not been fully clarified. In the present study, comparative proteomics analysis of two pairs of isogenic vancomycin-susceptible  S. aureus  (VSSA) and hVISA strains isolated from two patients identified five differentially expressed proteins, IsaA, MsrA2, Asp23, GpmA, and AhpC, present in both isolate pairs. All the proteins were up-regulated in the hVISA strains. These proteins were analyzed in six pairs of isogenic VSSA and hVISA strains, and unrelated VSSA (n = 30) and hVISA (n = 24) by real-time quantitative reverse transcriptase–PCR (qRT–PCR). Of the six pairs of isogenic strains,  isaA ,  msrA2  and  ahpC  were up-regulated in all six hVISA strains; whereas  asp23  and  gpmA  were up-regulated in five hVISA strains compared with the VSSA parental strains. In the unrelated strains, statistical analyses showed that only  isaA  was significantly up-regulated in the hVISA strains. Analysis of the five differentially expressed proteins in 15 pairs of persistent VSSA strains by qRT–PCR showed no differences in the expression of the five genes among the persistent strains, suggesting that these genes are not associated with persistence infection. Our results indicate that increased expression of  isaA  may be related to hVISA resistance.

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Comparative Proteomics-Based Identification of Genes Associated with Glycopeptide Resistance in Clinically Derived Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Strains