Prenylated flavonoids combat metabolically dormant methicillin-resistant <i>Staphylococcus aureus</i> by targeting FarR

<p>Antibiotic resistance and bacterial persistence threaten global health, with methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) being a particularly challenging pathogen. In this work, 3'-<i>C</i>-geranylphloretin (GP), a prenylated phenolic compound, showed better bactericidal activity against dormant MRSA cells than vancomycin. It significantly decreased bacterial loads, lung index, and improved pathological deterioration mediated by MRSA infection <i>in vivo</i>, and showed good safety to normal mice. Bacterial clearance was directly observed by two-photon excitation microscopy. GP disrupted bacterial persistence by targeting the transcriptional regulator FarR, which activated fatty acid and energy metabolism. Besides, GP-induced cell membrane disruption and apoptosis-like cell death in MRSA are caused by chromosomal condensation, reactive oxygen species (ROS) accumulation, and caspase-3/7 activation. Our research holds potential for anti-persister drug development.</p>