CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China.
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Angew Chem Int Ed Engl. 2019 May 13;58(20):6678-6682. doi: 10.1002/anie.201902210. Epub 2019 Apr 9.
In the antibiotics arsenal, vancomycin is a last resort for the treatment of intractable infections. However, this situation is under threat because of the increasing appearance of vancomycin-resistant bacteria (VRB). Herein, we report a series of novel vancomycin derivatives carrying a sulfonium moiety. The sulfonium-vancomycin derivatives exhibited enhanced antibacterial activity against VRB both in vitro and in vivo. These derivatives also exhibited activity against some Gram-negative bacteria. The sulfonium modification enhanced the interaction of vancomycin with the bacterial cell membrane and disrupts membrane integrity. Furthermore, the in vivo pharmacokinetic profile, stability, and toxicity of these derivatives demonstrated good druggability of the sulfonium-vancomycin analogues. This work provides a promising strategy for combating drug-resistant bacterial infection, and advances the knowledge on sulfonium derivatives for structural optimization and drug development.
在抗生素武器库中，万古霉素是治疗难治性感染的最后手段。然而，由于越来越多的耐万古霉素细菌（VRB）的出现，这种情况受到了威胁。在此，我们报告了一系列携带𬭸基部分的新型万古霉素衍生物。这些磺胺-万古霉素衍生物在体外和体内均表现出增强的抗 VRB 活性。这些衍生物还对一些革兰氏阴性菌具有活性。磺胺基修饰增强了万古霉素与细菌细胞膜的相互作用，并破坏了膜的完整性。此外，这些衍生物的体内药代动力学特征、稳定性和毒性表明磺胺-万古霉素类似物具有良好的成药性。这项工作为对抗耐药性细菌感染提供了一个有前途的策略，并为磺胺衍生物的结构优化和药物开发提供了相关知识。
