National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Cell Chem Biol. 2024 Nov 21;31(11):1874-1884.e6. doi: 10.1016/j.chembiol.2024.06.017. Epub 2024 Jul 31.
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我们发现具有独特抗菌机制的新抗生素。由于对抗菌活性缺乏全面了解以及新靶点的挖掘，新的靶点挖掘对于开发抗生素是必不可少的。植物-微生物抗生素是一种很有吸引力的未充分开发的来源，因为对其抗菌活性和新靶点的挖掘都知之甚少。在这里，我们合成了一系列与植物根相关的荧光假单胞菌的邻苯三酚衍生物，用于进行结构-活性关系分析。值得注意的是，2,4-二丙基邻苯三酚（DPPG）对多种革兰氏阳性菌显示出有效的杀菌活性。重要的是，机制研究表明，DPPG 与 II 型 NADH 脱氢酶（NDH-2）结合，NDH-2 是一种在电子传递链（ETC）中催化 NADH 向醌转移电子的必需酶，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 在体内的疗效。我们的研究结果不仅为治疗多药耐药病原体提供了一种独特的抗生素先导化合物，还确定了一个有前途的抗菌靶点。
