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.

全球抗生素耐药性危机需要紧急解决方案。一种创新方法涉及用佐剂或增强剂增强抗生素和非抗生素药物的作用。这些膜活性增强剂的一个主要缺点是它们的生物相容性有限，因为它们难以区分原核和真核膜。本研究报告了具有谷胱甘肽触发分解机制的双作用寡聚脒 ( OA1 ) 增强剂的化学生物学研究。 OA1与其他抗菌分子结合时，表现出三重靶向机制，包括细胞膜破坏、DNA靶向和细胞内酶抑制。这种多靶点机制不仅增强了体外和体内对抗生素耐药“ESKAPE”病原体的根除，而且还抑制了细菌耐药性的发展。此外， OA1通过创造氧化环境来维持其在细菌细胞中的活性，而在哺乳动物细胞中由于高谷胱甘肽水平而迅速分解。这些机制见解和设计原则可能为开发新型抗菌药物和有效的抗耐药联合疗法提供可行的方法。