Novel Aryl Sulfonium Modification on Vancomycin to Tackle MRSA and VRE In Vitro and In Vivo through Dual Enhanced Cell-Wall and Membrane Inhibition

Gram-positive superbugs resistant to methicillin and vancomycin pose a severe threat to global public health, urgently demanding novel therapeutic strategies. Herein, we rationally designed and synthesized vancomycin derivatives modified with diverse aryl sulfonium moieties to reactivate its antibacterial potency. By optimizing the sulfonium-based SAR, we got derivatives 2-3 orders of magnitude more active in vitro than vancomycin. Subsequently, preliminary toxicity evaluations for the optimal derivative, <b>7e</b>, indicated a favorable therapeutic index, while pharmacokinetic assays revealed its good properties, suggesting great drug-like potential. Notably, <b>7e</b> showed extremely potent in vivo protection efficacy by only a single-dose treatment in the challenging methicillin-resistant <i>Staphylococcus aureus</i> and VRE lethal sepsis mice models. Moreover, two independent and synergistic mechanisms of action were uncovered: membrane perturbation and enhanced cell wall biosynthesis inhibition. These findings revealed the unknown role of sulfonium strategy in vitro and in vivo and positioned <b>7e</b> as a promising candidate for future development.