The mechanism of high methicillin resistance in Staphylococcus aureus

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Methicillin resistance in Staphylococcus aureus is due to the acquisition of the low-affinity penicillin binding protein, PBP2A, encoded by mecA. However, there is lack of correlation between resistance levels and amount of PBP2A production leading to the conclusion that resistance to high levels of methicillin depends, in addition to PBP2A, on chromosomally encoded factors that are responsible for the strain-specific differences in resistance. The present study aims to investigate the factors affecting high methicillin resistance in MRSA. The study was started with isolating a set of isogenic MRSA strains with different level of methicillin resistance, and their whole genome sequences were determined. By comparing the genome sequence among the set of strains, candidate genes involved in high methicillin-resistant phenotype were identified and evaluated. Secondly, the genes identified as high methicillin-resistance associated in both this and our previous study, such as hmrA, hmrB, mgrA, graF and msrA2, were overexpressed in S.aureus to rise the level of methicillin resistance, and their transcriptional profiles for whole genome scale were compared each other, then the commonly regulated genes were identified to clarify the regulatory network of high methicillin resistance (HMR). The study conclusions are : 1) Fully expression of two component regulator system vraSR is necessary for HMR ; 2) regulatory gene sarH1 is deeply involved in HMR phenotype and 3) a novel mechanism, regulatory flip-flop genome inversion for HMR, was identified whereby HMR can achieved without chromosome mutation, but the detail deeded to be investigated.