Chemical Evolution of Natural Product for Discovery and Mechanistic Exploration of Antibiotic against MRSA

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) is the most threatening infectious resistant bacterium worldwide, thus the discovery of effective antibiotics against MRSA is a critical global priority. In this study, we report the chemical evolution of a natural product to discover a novel and potent antibiotic candidate. Specifically, neocryptotanshinone was semisynthetically modified, and its enantiomeric derivative (<i>S</i>)-<b>7n</b> demonstrated pronounced efficacy in vitro and in vivo for treating MRSA infection. This candidate was effective against vancomycin-resistant <i>S. aureus</i> (VRSA) and various clinical MRSA isolates, while exhibiting low toxicity. Mechanistic exploration suggests that (<i>S</i>)-<b>7n</b> exerts a dual antibacterial action, combining selective membrane depolarization with perturbation of the transcriptional regulator TetR/AcrR, likely independent of classical efflux pump control. This dual mechanism facilitates potent biofilm eradication, bacteria growth inhibition, and synergistic activity with specific antibiotics. Collectively, this work establishes (<i>S</i>)-7n as a promising, mechanistically novel lead compound and provides a natural product-inspired strategy to overcome MRSA resistance.