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, 7e, indicated a favorable therapeutic index, while pharmacokinetic assays revealed its good properties, suggesting great drug-like potential. Notably, 7e showed extremely potent in vivo protection efficacy by only a single-dose treatment in the challenging methicillin-resistant Staphylococcus aureus 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 7e as a promising candidate for future development.

耐甲氧西林（methicillin）与万古霉素（vancomycin）耐药的革兰氏阳性超级细菌对全球公共卫生构成严重威胁，亟需新型治疗策略。在此，我们通过理性设计并合成了携带有多样芳基锍基团修饰的万古霉素衍生物，以恢复其抗菌活性。通过优化基于锍基团的构效关系（Structure-Activity Relationship, SAR），我们获得的衍生物在体外的抗菌活性较万古霉素提升2至3个数量级。随后，对最优衍生物7e开展的初步毒性评估显示其具备良好的治疗指数，药代动力学实验则证实其拥有优良的成药性特征，提示其具备极高的药物开发潜力。值得注意的是，在致死性耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus）与耐万古霉素肠球菌（vancomycin-resistant Enterococcus, VRE）败血症小鼠模型中，仅单剂量给药的7e便展现出极强的体内保护效果。此外，本研究揭示了两种独立且协同的抗菌作用机制：膜扰动与增强的细胞壁生物合成抑制作用。上述发现阐明了锍基策略在体内外抗菌中的未知作用，并将7e确立为未来药物开发的极具前景的候选化合物。