Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H₂S)–mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H₂S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H₂S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.

对所有临床抗生素的新兴耐药性需要下一代治疗方法。在此，我们报告了一种针对细菌硫化氢 (H ₂ S) 介导的防御系统的有效抗菌策略。我们确定胱硫醚 γ-裂解酶 (CSE) 是两种主要人类病原体（金黄色葡萄球菌和铜绿假单胞菌）中 H ₂ S 的主要产生者，并发现了抑制细菌 CSE 的小分子。这些抑制剂在体外和小鼠感染模型中增强了针对两种病原体的杀菌抗生素。 CSE 抑制剂还可以抑制细菌耐受性，破坏生物膜的形成，并大幅减少抗生素治疗后存活的细菌数量。我们的结果确定细菌 H ₂ S 是一种多功能防御因子，CSE 是多功能抗生素增强剂的药物靶点。