近日，中国科学院上海药物研究所管栋梁及其课题组的研究开发出了一种合理设计的具有胶束自组装的磺酸脂糖肽通过双重增强的细胞壁膜抑制和T7SS蛋白下调来对抗多药耐药。这一研究成果于2025年4月8日发表在国际顶尖学术期刊《美国化学会杂志》上。

耐多药革兰氏阳性超级细菌对全球公共卫生构成重大威胁，迫切需要新型抗生素的出现。本研究合理设计合成了三种由万古霉素衍生的联苯磺酸脂糖肽类，以对抗这种耐药性。其中，最有希望的衍生物BD-V-2在体外对多种难治性菌株表现出出色的活性。值得注意的是，在MRSA和VREm （vanA）诱导的两种极具挑战性的致死性脓毒症模型中，仅7 mg/kg和2.5 mg/kg的单次低剂量给药，就能对感染小鼠实现完全保护，生动地展示了其强大的体内功效。

此外，其体内药代动力学特征和毒性评估表明其具有良好的药理作用。有趣的是，BD-V-2被发现赋予胶束一种新的自组装特性。此外，还阐明了通过磷脂酰甘油（PG）相互作用靶向细菌膜和细胞壁的独立和协同作用机制，分别通过脂质II上的两个结合位点肽间桥和焦磷酸盐基序。令人惊讶的是，BD-V-2能够显著下调VII型分泌系统蛋白的表达，揭示了糖肽类抗生素前所未有的抗毒机制。总的来说，这些发现揭示了迄今为止未知的磺化策略的作用，并将BD-V-2确定为未来药物开发的极具前景的候选药物。

附：英文原文

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

Author: Yuanyuan Xie, Xiaowen Wang, Fang Li, Zhifu Chen, Qun Li, Shuhui Liu, Jingwen Zhang, Hui Wang, Zhenyong Wu, Jinyong Zhang, Dongliang Guan

Issue&Volume: April 8, 2025

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

DOI: 10.1021/jacs.4c18630

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c18630