RESTORATION OF ANTIBIOTIC SUSCEPTIBILITY IN METHICILLIN‐RESISTANT STAPHYLOCOCCUS AUREUS BY TARGETING MECR1 WITH A PHOSPHOROTHIOATE DEOXYRIBOZYME

SUMMARY Methicillin resistance in Staphylococcus aureus is mediated by the mecA gene. The mecA gene encodes a penicillin‐binding protein (PBP2a) possessing low β‐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 β‐lactams. 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. 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. 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 β‐lactam antibiotics.