Chemical biology investigation of a triple-action,smart-decomposition antimicrobial booster based-combination therapy against“ESKAPE”pathogens  

作　　者：Min Wang Huangsheng Pu Yangfan Xu Chenxuan Wu Yuanxin Gu Qingyun Cai Guoxing Yin Peng Yin Chunhui Zhang Wing-Leung Wong Muyang Wan Yugang Bai Xinxin Feng 

机构地区：[1]State Key Laboratory of Chem-/Bio-Sensing and Chemometrics,Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology,and School of Chemistry and Chemical Engineering,Hunan University,Changsha 410082,China [2]College of Biology,Hunan University,Changsha 410082,China [3]College of Advanced Interdisciplinary Studies&Hunan Provincial Key Laboratory of Novel Nano Optoelectronic Information Materials and Devices,National University of Defense Technology,Changsha 410073,China [4]Nanhu Laser Laboratory,National University of Defense Technology,Changsha 410073,China [5]Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research(Ministry of Education),College of Chemistry and Chemical Engineering,Hunan Normal University,Changsha 410081,China [6]State Key Laboratory of Chemical Biology and Drug Discovery,Department of Applied Biology and Chemical Technology,The Hong Kong Polytechnic University,Hong Kong SAR 999077,China [7]Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs,The Third Hospital of Changsha(The Affiliated Changsha Hospital of Hunan University),Changsha 410015,China

出　　处：《Science China Chemistry》2024年第9期3071-3082,共12页中国科学（化学英文版）

基　　金：supported by the National Key Research and Development Program of China(2023YFD1800100 to Feng X and Bai Y);the National Natural Science Foundation of China(22177031 to Feng X,92163127 to Bai Y,82102415 to Wan M,and 82304277 to Zhang C);the Natural Science Foundation of Hunan Province(2024JJ4007 and 2024RC3078 to Feng X,2022RC1107 and 2024JJ2010 to Bai Y);the Natural Science Foundation of Changsha(kq2208050 to Zhang C);the Health and Medical Research Fund(HMRF),Hong Kong SAR(22210412to Wong WL);the Independent Research Project of the College of Advanced Interdisciplinary Studies of NUDT(22-ZZKY-03 to Pu H);the Project of Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs(2023TP1013)。

摘　　要：The global antibiotic resistance crisis necessitates urgent solutions.One innovative approach involves potentiating antibiotics and non-antibiotic drugs with adjuvants or boosters.A major drawback of these membrane-active boosters is their limited biocompatibility,as they struggle to differentiate between prokaryotic and eukaryotic membranes.This study reports the chemical biology investigation of a dual-action oligoamidine(OA1)booster with a glutathione-triggered decomposition mechanism.OA1,when combined with other antimicrobial molecules,exhibits a triple-targeting mechanism including cell membrane disruption,DNA targeting,and intracellular enzyme inhibition.This multi-targeting mechanism not only enhances the in vitro and in vivo eradication of antibiotic-resistant“ESKAPE”pathogens,but also suppresses the development of bacterial resistance.Furthermore,OA1 maintains its activity in bacterial cells by creating an oxidative environment,while it quickly decomposes in mammalian cells due to high glutathione levels.These mechanistic insights and design principles may provide a feasible approach to develop novel antimicrobial agents and effective anti-resistance combination therapies.

关 键 词：antimicrobial booster oligoamidine membrane disruption DNA targeting triggered degradation anti-resistance 

分 类 号：R914[医药卫生—药物化学]