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.