Study on the Mechanism of Berberine Reversing MRSA Resistance to β-Lactam Antibiotics by Inhibiting blaZ Expression

This study elucidates a novel mechanism by which the natural product berberine (BBR) reverses methicillin-resistant Staphylococcus aureus (MRSA) resistance to β-lactam antibiotics. It was established that BBR interferes with the BlaR1/BlaI regulatory pathway by means of downregulating the signal sensor gene blaR1 and the repressor gene blaI, thereby significantly suppressing the expression of the β-lactamase-encoding gene blaZ at the transcriptional level. The combination susceptibility testing demonstrated that BBR and Oxacillin exhibited synergistic or additive effects in 76.92% of the bacterial strains that were tested. This enhanced efficacy was closely associated with the presence of the blaZ gene. Molecular docking and dynamics simulations further confirmed that BBR stably binds to the active site of the BlaZ protein. These findings systematically clarify the multi-target mechanism of BBR as an antibiotic synergist and provide an important theoretical basis for developing combination therapeutic strategies against MRSA. BBR suppresses β-lactamase production by disrupting the BlaR1/BlaI regulatory pathway, downregulating blaR1 and blaI, thereby inhibiting blaZ transcription. BBR restores susceptibility to Oxacillin, exhibiting synergistic or additive effects in 76.92% of clinical MRSA strains, with efficacy dependent on bacterial blaZ gene presence.