Restoration of oxacillin susceptibility in methicillin-resistant Staphylococcus aureus by blocking the MecR1-mediated signaling pathway

The signal transducing integral membrane protein, MecR1 helps initiate the expression of the antibiotic-resistant gene mecA, which encodes the penicillin-binding protein 2a. MecA participates in the beta-lactam resistance of methicillin-resistant Staphylococcus aureus (MRSA). Blocking the MecR1 regulatory pathway may be a novel strategy to combat MRSA. In this study, we introduced an antisense phosphothioate oligodeoxynucleotide (PS-ODN) targeting MecR1 mRNA into the MRSA strain WHO-2, which led to a significant reduction of both MecR1 and PBP2a mRNAs in a concentration-dependent manner. Consequently, the susceptibility of S. aureus WHO-2 to the beta-lactam antibiotic oxacillin was restored significantly. Our results indicate that blocking the mecR1-mecI-mecA signaling pathway via an antisense approach might be a viable strategy to restore the susceptibility of MRSA to the existing beta-lactam antibiotics.