A Rationally Designed Sulfonium Lipoglycopeptide with Micelles Self-Assembly to Combat Multidrug Resistance via Dual Enhanced Cell Wall-Membrane Inhibition and T7SS Proteins Downregulation

• DOI: 10.1021/jacs.4c18630
• Publication Date: 2025-04-08T08:17:05Z
• Authors: Yuanyuan Xie; Xiaowen Wang; Fang Li; Zhifu Chen; Qun Li; Shuhui Liu; Jingwen Zhang; Hui Wang; Zhenyong Wu; Jinyong Zhang; Dongliang Guan
• Keywords: Sulfonium; Cell membrane

Multidrug-resistant Gram-positive superbugs pose a significant menace to global public health, urgently demanding the advent of novel antibiotics. In this study, three biphenyl sulfonium lipoglycopeptides derived from vancomycin were rationally designed and synthesized combat such resistance. Among them, most promising derivative, BD-V-2, exhibited outstanding in vitro activity against diverse array refractory strains. Notably, two highly challenging lethal sepsis models induced by MRSA VREm (vanA), BD-V-2 achieved complete protection infected mice with remarkably low single-dose administrations merely 7 2.5 mg/kg, respectively, vividly demonstrating its potent vivo efficacy. Furthermore, pharmacokinetic profile toxicity assessment indicated favorable druggability. Interestingly, was found impart self-assembly property into micelles. addition, independent synergistic mechanisms action targeting bacterial membrane, via phosphatidylglycerol (PG) interaction, cell wall, more binding sites on lipid II, interpeptide bridge pyrophosphate motif, elucidated. Astonishingly, capable significantly downregulating expression type VII secretion system proteins, uncovering an unprecedented antivirulence mechanism for glycopeptide Collectively, these findings unraveled hitherto unknown roles strategy established as prospective candidate future pharmaceutical development.