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A Broad-Spectrum Abietane Diterpenoid Derivative that Targets Lipid II Cycle and Bacterial Membrane to Combat Multidrug Resistance

文献类型：期刊论文

作者Li, Yajing7,8; Yin, Ziqi5,6; Liu, Shuhui7; Bian, Xiaolei7; Chen, Zhifu4; Ren, Zhiwei7,8; Chen, Dianyan1,3; Fu, Xiaomei8; Zhang, Jinyong4; Feng, Xinxin6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-10-09
卷号68期号:19页码:20487-20505
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c01657
通讯作者Fu, Xiaomei(smilefxm@163.com) ; Zhang, Jinyong(zhangjy198217@126.com) ; Feng, Xinxin(xinxin_feng@hnu.edu.cn) ; Guan, Dongliang(dlguan@baridd.ac.cn)
英文摘要The escalating threat of drug-resistant superbugs has urgently necessitated the development of antibiotics with novel scaffolds and mechanisms. Herein, we rationally designed and synthesized novel abietane diterpenoid derivatives from carnosic acid (CA) inspired by the "amine/guanidine" modification strategy. Most derivatives designed exhibited greater activities than CA and even vancomycin (similar to 2-64-fold). The optimized 4c demonstrated ultrabroad-spectrum activity against MRSA, VRE, CRAB, and mycobacteria, coupled with desirable properties of rapid bactericidal ability, low resistance development propensity, and good safety profile. Mechanistic studies first revealed a novel independent and synergistic "cell wall-membrane" dual inhibitory mechanism, respectively, via interfering with bacterial lipid II cycle and inducing membrane permeabilization and depolarization. Subsequent in vivo studies elucidated that 4c demonstrated favorable efficacy in zebrafish and mouse infection models. Collectively, these findings highlight the antimicrobial potential of abietane diterpenoids derived from CA and identify 4c as a promising drug candidate against drug-resistant bacterial infections.
WOS关键词CARNOSIC ACID ; CELL-WALL ; VANCOMYCIN
资助项目Science Fund for Distinguished Young Scholars of Shandong Province[82304272] ; Science Fund for Distinguished Young Scholars of Shandong Province[32170938] ; National Natural Science Foundation of China[ZR2024QH641] ; Shandong Province Science Foundation for Youths[2024JJ4007] ; Natural Science Foundation of Hunan Province[2024RC3078] ; Science Fund for Distinguished Young Scholars of Hunan Province ; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery ; Nanjing Cantech Microbial Technology Co. Ltd.
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001579178400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321579]  
专题中国科学院上海药物研究所
通讯作者Fu, Xiaomei; Zhang, Jinyong; Feng, Xinxin; Guan, Dongliang
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
4.Army Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing 400038, Peoples R China
5.Hunan Univ, Sch Chem & Chem Engn, Changsha 410082, Hunan, Peoples R China
6.Hunan Univ, Hunan Prov Key Lab Biomacromolecular Chem Biol, State Key Lab Chemo Biosensing & Chemometr, Changsha 410082, Hunan, Peoples R China
7.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
8.Jiangxi Univ Chinese Med, Sch Pharm, Nanchang 330004, Jiangxi, Peoples R China
推荐引用方式
GB/T 7714		 Li, Yajing,Yin, Ziqi,Liu, Shuhui,et al. A Broad-Spectrum Abietane Diterpenoid Derivative that Targets Lipid II Cycle and Bacterial Membrane to Combat Multidrug Resistance[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(19):20487-20505.
APA Li, Yajing.,Yin, Ziqi.,Liu, Shuhui.,Bian, Xiaolei.,Chen, Zhifu.,...&Guan, Dongliang.(2025).A Broad-Spectrum Abietane Diterpenoid Derivative that Targets Lipid II Cycle and Bacterial Membrane to Combat Multidrug Resistance.JOURNAL OF MEDICINAL CHEMISTRY,68(19),20487-20505.
MLA Li, Yajing,et al."A Broad-Spectrum Abietane Diterpenoid Derivative that Targets Lipid II Cycle and Bacterial Membrane to Combat Multidrug Resistance".JOURNAL OF MEDICINAL CHEMISTRY 68.19(2025):20487-20505.

入库方式： OAI收割

来源：上海药物研究所

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