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

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Science China Chemistry 2024年第9期67卷 3071-3082页

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 State Key Laboratory of Chem-/Bio-Sensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biologyand School of Chemistry and Chemical EngineeringHunan UniversityChangsha 410082China College of Biology Hunan UniversityChangsha 410082China College of Advanced Interdisciplinary Studies&Hunan Provincial Key Laboratory of Novel Nano Optoelectronic Information Materials and Devices National University of Defense TechnologyChangsha 410073China Nanhu Laser Laboratory National University of Defense TechnologyChangsha 410073China Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research(Ministry of Education) College of Chemistry and Chemical EngineeringHunan Normal UniversityChangsha 410081China State Key Laboratory of Chemical Biology and Drug Discovery Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong SAR 999077China Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs The Third Hospital of Changsha(The Affiliated Changsha Hospital of Hunan University)Changsha 410015China

The global antibiotic resistance crisis necessitates urgent *** 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 *** study reports the chemical biology investigation of a dual-action oligoamidine(OA1)booster with a glutathione-triggered decomposition ***1,when combined with other antimicrobial molecules,exhibits a triple-targeting mechanism including cell membrane disruption,dna targeting,and intracellular enzyme *** 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 ***,OA1 maintains its activity in bacterial cells by creating an oxidative environment,while it quickly decomposes in mammalian cells due to high glutathione *** 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

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