YZ462 exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus through bacterial membrane disruption

The global rise of antibiotic resistance presents a critical public health challenge, with Staphylococcus aureus being a leading cause of hospital- and community-acquired infections. Methicillin-resistant S. aureus (MRSA) is particularly concerning due to its high prevalence, multidrug resistance, and association with severe morbidity and mortality. Developing novel small-molecule antimicrobial agents with reduced resistance susceptibility is essential to combat these infections. From our in-house compound library, we identified YZ462, a heteroaromatic-aryl scaffold compound, demonstrating potent antibacterial activity and low toxicity. YZ462 showed strong anti-MRSA effects through bacterial membrane disruption, increased permeability, and induction of endogenous ROS production. In vitro, it effectively killed both log-phase and stationary-phase MRSA while inhibiting biofilm formation and disrupting established biofilms. In vivo studies revealed significant reduction of bacterial loads and improved survival rates in infected animal models. Importantly, the major S. aureus membrane component cardiolipin (CL) directly interacted with YZ462 and attenuated its antibacterial activity, suggesting CL as a potential molecular target. Our study establishes YZ462 as a promising small-molecule candidate for MRSA treatment, featuring a unique mechanism of membrane disruption and ROS induction. These results confirm its potent antimicrobial activity and demonstrate therapeutic potential against MRSA infections.