Restoration of antibiotic susceptibility in methicillin-resistant Staphylococcus aureus by targeting mecR1 with a phosphorothioate deoxyribozyme.

1. Methicillin resistance in Staphylococcus aureus is mediated by the mecA gene. The mecA gene encodes a penicillin-binding protein (PBP2a) possessing low beta-lactam affinity. Transcription of mecA is regulated by a signal transduction system consisting of the sensor/transducer MecR1. Disruption of the MecR1 regulatory pathway may inhibit mecA expression and restore methicillin-resistant Staphylococcus aureus (MRSA) susceptibility to beta-lactams. 2. In the present study, a phosphorothioate deoxyribozyme (named PS-DRz147) specifically targeting MecR1 mRNA was designed, synthesised and introduced into the MRSA strain WHO-2. 3. The expression of mecR1 and mecA was inhibited by PS-DRz147 in a concentration-dependent manner. Consequently, the susceptibility of WHO-2 colonies to the antibiotic oxacillin was restored. 4. The results of the present study indicate that blockade of the MecR1-MecI-MecA signalling pathway with an mecR1-targeted DNAzyme can restore the susceptibility of MRSA to existing beta-lactam antibiotics.