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Single Amine or Guanidine Modification on Norvancomycin and Vancomycin to Overcome Multidrug-Resistance through Augmented Lipid II Binding and Increased Membrane Activity

文献类型：期刊论文

作者Bian, Xiaolei2; Chen, Zhifu3; Li, Fang2,4; Xie, Yuanyuan2,4; Li, Yi2; Luo, Youhong1; Zou, Xiangman4; Wang, Hui6; Zhang, Jingwen1; Wang, Xiaowen2,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-11-06
卷号67期号:22页码:20639-20663
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02196
通讯作者Wang, Xiaowen(xwwang@baridd.ac.cn) ; Zhang, Jinyong(zhangjy198217@126.com) ; Guan, Dongliang(guandongliang@simm.ac.cn)
英文摘要Vancomycin and norvancomycin have diminished antibacterial efficacy due to acquired or intrinsic resistance from mutations in the terminal dipeptide of lipid II in Gram-positive bacteria or failure to penetrate into the periplasm in Gram-negative bacteria. Herein, we rationally designed and synthesized a series of vancomycin analogues bearing single amine or guanidine functionality, altering various linkers and modification sites, to combat the resistance. Extensive antibacterial screening was performed to delineate a comprehensive SAR. Many derivatives revitalized the activity in vitro, exhibiting a 4-128-fold or 2-16-fold enhancement against the acquired or intrinsic resistance with lower toxicity. Significantly, the optimal compound 4g demonstrated greater pharmacokinetic and pharmacodynamic profiles. Further studies uncovered additional independent and synergistic mechanisms for 4g, including the enhanced membrane activity and augmented inhibition of peptidoglycan biosynthesis via increased lipid II binding, highlighting its potential as a future lead candidate to replenish the glycopeptide antibiotic arsenal.
WOS关键词CELL-WALL ; DISCOVERY ; ANTIBIOTICS ; DERIVATIVES ; INHIBITION ; STRATEGY ; BACTERIA ; ANALOGS ; TARGET
资助项目National Natural Science Foundation of China[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[32170938] ; Shandong Province Medical and Health Science and Technology Development Project[82304272] ; National Natural Science Foundation of China (NSFC) ; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery ; Yantai Institute of Coastal Zone Research ; 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:001349077700001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/314339]  
专题中国科学院上海药物研究所
通讯作者Wang, Xiaowen; Zhang, Jinyong; Guan, Dongliang
作者单位1.Shandong Second Med Univ, Clin Res Ctr, Dept Endocrinol & Metab, Affiliated Hosp,Shandong Prov Key Med & Hlth Disci, Weifang 261031, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Army Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing 400038, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Nanjing Cantech Microbial Technol Co Ltd, Nanjing 211100, Peoples R China
推荐引用方式
GB/T 7714		 Bian, Xiaolei,Chen, Zhifu,Li, Fang,et al. Single Amine or Guanidine Modification on Norvancomycin and Vancomycin to Overcome Multidrug-Resistance through Augmented Lipid II Binding and Increased Membrane Activity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(22):20639-20663.
APA Bian, Xiaolei.,Chen, Zhifu.,Li, Fang.,Xie, Yuanyuan.,Li, Yi.,...&Guan, Dongliang.(2024).Single Amine or Guanidine Modification on Norvancomycin and Vancomycin to Overcome Multidrug-Resistance through Augmented Lipid II Binding and Increased Membrane Activity.JOURNAL OF MEDICINAL CHEMISTRY,67(22),20639-20663.
MLA Bian, Xiaolei,et al."Single Amine or Guanidine Modification on Norvancomycin and Vancomycin to Overcome Multidrug-Resistance through Augmented Lipid II Binding and Increased Membrane Activity".JOURNAL OF MEDICINAL CHEMISTRY 67.22(2024):20639-20663.

入库方式： OAI收割

来源：上海药物研究所

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