The rapid rise of antibiotic resistance calls for the discovery of new antibiotics with distinct antibacterial mechanisms. New target mining is indispensable for developing antibiotics. Plant-microbial antibiotics are appealing to underexplored sources due to a dearth of comprehensive understanding of antibacterial activity and the excavation of new targets. Here, a series of phloroglucinol derivatives of plant-root-associated Pseudomonas fluorescens were synthesized for structure-activity relationship analysis. Notably, 2,4-diproylphloroglucinol (DPPG) displayed efficient bactericidal activity against a wide range of gram-positive bacteria. Importantly, mechanistic study exhibits that DPPG binds to type II NADH dehydrogenase (NDH-2), an essential enzyme catalyzing the transfer of electrons from NADH to quinones in the electron transport chain (ETC), blocking electron transfer in S. aureus. Last, we validated the efficacy of DPPG in vivo through animal infection models. Our findings not only provide a distinct antibiotic lead to treat multidrug resistant pathogens but also identify a promising antibacterial target.

抗生素耐药性的迅速上升要求发现具有独特抗菌机制的新抗生素。新靶点的挖掘对于抗生素的开发是必不可少的。由于缺乏对抗菌活性的全面了解和新靶点的挖掘，植物微生物抗生素对尚未开发的来源很有吸引力。在这里，合成了一系列植物根相关荧光假单胞菌的间苯三酚衍生物，用于结构-活性关系分析。值得注意的是，2,4-二丙基间苯三酚（DPPG）对多种革兰氏阳性菌表现出有效的杀菌活性。重要的是，机理研究表明 DPPG 与 II 型 NADH 脱氢酶 (NDH-2) 结合，这是一种催化电子从 NADH 转移到电子传递链 (ETC) 中醌类的必需酶，从而阻断金黄色葡萄球菌中的电子传递。最后，我们通过动物感染模型验证了DPPG的体内功效。我们的研究结果不仅为治疗多重耐药病原体提供了独特的抗生素线索，而且还确定了一个有前途的抗菌靶点。