Single Amine or Guanidine Modification on Norvancomycin and Vancomycin to Overcome Multidrug-Resistance through Augmented Lipid II Binding and Increased Membrane ActivityClick to copy article linkArticle link copied!
- Xiaolei BianXiaolei BianShandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, ChinaMore by Xiaolei Bian
- Zhifu ChenZhifu ChenNational Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing 400038, ChinaMore by Zhifu Chen
- Fang LiFang LiShandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, ChinaShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Rd, Pudong, Shanghai 201203, ChinaMore by Fang Li
- Yuanyuan XieYuanyuan XieShandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, ChinaShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Rd, Pudong, Shanghai 201203, ChinaMore by Yuanyuan Xie
- Yi LiYi LiShandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, ChinaMore by Yi Li
- Youhong LuoYouhong LuoDepartment of Endocrinology and Metabolism, Clinical Research Center, Shandong Provincial Key Medical and Health Discipline of Endocrinology, Affiliated Hospital of Shandong Second Medical University, Weifang 261031, ChinaMore by Youhong Luo
- Xiangman ZouXiangman ZouShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Rd, Pudong, Shanghai 201203, ChinaMore by Xiangman Zou
- Hui WangHui WangNanjing Cantech Microbial Technology Co. Ltd., No. 18, Zhilan Rd, Jiangning, Nanjing 211100, ChinaMore by Hui Wang
- Jingwen ZhangJingwen ZhangDepartment of Endocrinology and Metabolism, Clinical Research Center, Shandong Provincial Key Medical and Health Discipline of Endocrinology, Affiliated Hospital of Shandong Second Medical University, Weifang 261031, ChinaMore by Jingwen Zhang
- Xiaowen Wang*Xiaowen Wang*Email: [email protected]Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, ChinaShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Rd, Pudong, Shanghai 201203, ChinaMore by Xiaowen Wang
- Jinyong Zhang*Jinyong Zhang*Email: [email protected]National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing 400038, ChinaMore by Jinyong Zhang
- Dongliang Guan*Dongliang Guan*Email: [email protected]Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, ChinaShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Rd, Pudong, Shanghai 201203, ChinaUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, ChinaMore by Dongliang Guan
Abstract
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.
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