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Novel Aryl Sulfonium Modification on Vancomycin to Tackle MRSA and VRE In Vitro and In Vivo through Dual Enhanced Cell-Wall and Membrane Inhibition

文献类型：期刊论文

作者Xie, Yuanyuan5,6,8; Wang, Xiaowen5,6; Chang, Taopeng5; Chen, Zhifu7; Luo, Youhong1; Zhang, Jingwen1; Wang, Hui2; Dong, Jinhua8; Chen, Feifei4,6; Zhang, Jinyong7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-04-12
卷号68期号:8页码:8310-8329
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c03028
通讯作者Dong, Jinhua(jhdong@syphu.edu.cn) ; Chen, Feifei(feifeichen@simm.ac.cn) ; Zhang, Jinyong(zhangjy198217@126.com) ; Guan, Dongliang(guandongliang@simm.ac.cn)
英文摘要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.
WOS关键词ALA-D-ALA ; RESISTANT STAPHYLOCOCCUS-AUREUS ; REENGINEERING VANCOMYCIN ; AGLYCON ; ANALOGS ; BIOSYNTHESIS ; BACTERIA ; STRATEGY
资助项目National Natural Science Foundation of China[82304272] ; National Natural Science Foundation of China[32170938] ; National Natural Science Foundation of China ; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery[2023705] ; Shanghai Postdoctoral Excellence Program[GZC20232847] ; Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation[202203060917] ; Shandong Province Medical and Health Science and Technology Development Project[ZXWH2170101] ; Shandong Province Medical and Health Science and Technology Development Project[Efm-HS-vb02] ; Shandong Province Medical and Health Science and Technology Development Project[KP-1] ; Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University ; Pharmaceutical Analysis and Quality Research Platform of Bohai Rim Advanced Research institute for Drug Discovery
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001465842200001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/317428]  
专题中国科学院上海药物研究所
通讯作者Dong, Jinhua; Chen, Feifei; Zhang, Jinyong; Guan, Dongliang
作者单位1.Shandong Second Med Univ, Affiliated Hosp, Clin Res Ctr, Dept Endocrinol & Metab,Shandong Prov Key Med & Hl, Weifang 261031, Peoples R China
2.Nanjing Cantech Microbial Technol Co Ltd, Nanjing 211100, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
7.Army Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing 400038, Peoples R China
8.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China
推荐引用方式
GB/T 7714		 Xie, Yuanyuan,Wang, Xiaowen,Chang, Taopeng,et al. Novel Aryl Sulfonium Modification on Vancomycin to Tackle MRSA and VRE In Vitro and In Vivo through Dual Enhanced Cell-Wall and Membrane Inhibition[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(8):8310-8329.
APA Xie, Yuanyuan.,Wang, Xiaowen.,Chang, Taopeng.,Chen, Zhifu.,Luo, Youhong.,...&Guan, Dongliang.(2025).Novel Aryl Sulfonium Modification on Vancomycin to Tackle MRSA and VRE In Vitro and In Vivo through Dual Enhanced Cell-Wall and Membrane Inhibition.JOURNAL OF MEDICINAL CHEMISTRY,68(8),8310-8329.
MLA Xie, Yuanyuan,et al."Novel Aryl Sulfonium Modification on Vancomycin to Tackle MRSA and VRE In Vitro and In Vivo through Dual Enhanced Cell-Wall and Membrane Inhibition".JOURNAL OF MEDICINAL CHEMISTRY 68.8(2025):8310-8329.

入库方式： OAI收割

来源：上海药物研究所

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