Psoralea corylifolia seed extract bakuchiol hijacks bacterial metabolism to induce oxygen-dependent membrane lipid peroxidation in methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) poses a global health threat due to limited therapeutic options and biofilm-mediated tolerance. Here, we demonstrated that bakuchiol (BAK), a meroterpenoid from Psoralea corylifolia seeds, exerted potent activity against MRSA through a novel membrane-targeting mechanism. MIC and time-kill assays evaluated BAK against clinical MRSA strains. Mechanisms were probed via ATP/ nitric oxide (NO) quantification, membrane lipid peroxidation, ROS detection, and phospholipid supplementation. The results revealed that BAK exhibited potent bactericidal activity against MRSA (MIC 2 μg/mL). Mechanistic studies showed BAK hijacked bacterial metabolism, suppressing ROS generation, but elevating the levels of ATP to fuel NO synthesis, driving oxygen-dependent membrane lipid peroxidation, ultimately causing membrane/functional damage and cell death. Crucially, the antibacterial activity of BAK was attenuated by rotenone, exogenous phospholipids, or under anaerobic conditions. Moreover, BAK maintained efficacy against biofilm MRSA, with distinct mechanistic advantages over conventional antibiotics. Collectively, BAK exploits bacterial metabolism to induce targeted membrane lipid peroxidation, representing a promising anti-infective agent against drug-resistant pathogens.