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Unanticipated Quinoline Modification on Vancomycin as an Effective Strategy to Alter the Antibacterial Profile and Combat Multidrug Resistance

文献类型：期刊论文

作者Chang, Taopeng7,8; Chen, Zhifu2; Sheng, Lishu8; Bian, Xiaolei8; He, Peng6; He, Xiao8; Liu, Shuhui8; Zhang, Jingwen1; Ren, Hao5; Zhang, Jinyong2
刊名JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
出版日期2025-11-19
卷号147期号:46页码:42670-42684
ISSN号0002-7863
DOI10.1021/jacs.5c14268
通讯作者Zhang, Jinyong(zhangjy198217@126.com) ; Guan, Dongliang(dlguan@baridd.ac.cn)
英文摘要Lipid II, referred to as the bacterial "Achilles' heel" and serving as the target of vancomycin, remains inaccessible to vancomycin in Gram-negative bacteria due to their outer membrane (OM) barrier, rendering it intrinsically ineffective against these pathogens. Herein, we serendipitously discovered that a simple, single quinoline moiety modification on vancomycin yields quinovancins, which not only restore vancomycin susceptibility against acquired vancomycin-resistant strains but also unexpectedly expand its antibacterial spectrum to encompass certain Gram-negative Enterobacteriaceae (e.g., Escherichia coli, Salmonella) in vitro and in vivo. Intriguingly, substitution with a naphthalene group failed to confer such activity. Mechanistically, quinovancins overcome acquired resistance through augmented "cell wall-membrane" dual inhibitions in Gram-positive bacteria. In Gram-negative bacteria, the quinoline moiety functions as a shuttle, facilitating vancomycin's transit across the OM to the Lipid II site without compromising OM integrity-distinct from conventional OM-disrupting pathways. Besides, the best quinovancin candidate 3d exhibits a synergistic sensitization effect to potentiate meropenem, particularly against carbapenem-resistant E. coli. Furthermore, 3d demonstrates favorable druggability, including rapid and scalable synthesis, great solubility, outperformed in vivo pharmacokinetic profiles, and good safety. This work provides an unanticipated but promising strategy that enables the secondary development of vancomycin to combat bacterial multidrug resistance.
WOS关键词ALA-D-ALA ; CELL-WALL BIOSYNTHESIS ; REENGINEERING VANCOMYCIN ; LIPID-II ; MEMBRANE ; BINDING ; BACTERIA ; AGLYCON ; ANALOGS
资助项目Shandong Province Science Foundation for Youths[ZR2024QH641] ; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery[NA] ; Key Technology Research and Development Program of Shandong Province[2025CXPT012] ; National Natural Science Foundation of China[32170938]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001611252900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321732]  
专题中国科学院上海药物研究所
通讯作者Zhang, Jinyong; Guan, Dongliang
作者单位1.Shandong Second Med Univ, Shandong Prov Key Med & Hlth Discipline Endocrinol, Dept Endocrinol & Metab, Clin Res Ctr,Affiliated Hosp, Weifang 261031, Shandong, Peoples R China
2.Army Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing 400038, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.South China Agr Univ, Coll Vet Med, State Key Lab Anim Dis Control & Prevent, Guangzhou 510642, Guangdong, Peoples R China
6.Fudan Univ, Shanghai Pudong Hosp, Pudong Med Ctr, Dept Pharm, Shanghai 201399, Peoples R China
7.Anhui Univ Chinese Med, Sch Pharm, Hefei 230038, Anhui, Peoples R China
8.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Chang, Taopeng,Chen, Zhifu,Sheng, Lishu,et al. Unanticipated Quinoline Modification on Vancomycin as an Effective Strategy to Alter the Antibacterial Profile and Combat Multidrug Resistance[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025,147(46):42670-42684.
APA Chang, Taopeng.,Chen, Zhifu.,Sheng, Lishu.,Bian, Xiaolei.,He, Peng.,...&Guan, Dongliang.(2025).Unanticipated Quinoline Modification on Vancomycin as an Effective Strategy to Alter the Antibacterial Profile and Combat Multidrug Resistance.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(46),42670-42684.
MLA Chang, Taopeng,et al."Unanticipated Quinoline Modification on Vancomycin as an Effective Strategy to Alter the Antibacterial Profile and Combat Multidrug Resistance".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.46(2025):42670-42684.

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来源：上海药物研究所

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