Department of Pathogen Biology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing 211166, China.
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Sci Adv. 2023 Aug 4;9(31):eadg5995. doi: 10.1126/sciadv.adg5995.
poses a severe public health problem as one of the vital causative agents of healthcare- and community-acquired infections. There is a globally urgent need for new drugs with a novel mode of action (MoA) to combat biofilms and persisters that tolerate antibiotic treatment. We demonstrate that a benzonaphthopyranone glycoside, chrysomycin A (ChryA), is a rapid bactericide that is highly active against persisters, robustly eradicates biofilms in vitro, and shows a sustainable killing efficacy in vivo. ChryA was suggested to target multiple critical cellular processes. A wide range of genetic and biochemical approaches showed that ChryA directly binds to GlmU and DapD, involved in the biosynthetic pathways for the cell wall peptidoglycan and lysine precursors, respectively, and inhibits the acetyltransferase activities by competition with their mutual substrate acetyl-CoA. Our study provides an effective antimicrobial strategy combining multiple MoAs onto a single small molecule for treatments of persistent infections.
作为医疗保健和社区获得性感染的重要病原体之一，它构成了严重的公共卫生问题。全球迫切需要具有新型作用机制 (MoA) 的新药来对抗能够耐受抗生素治疗的生物膜和持续存在的细菌。我们证明了苯并萘并吡喃酮糖苷，金霉素 A（ChryA），是一种快速杀菌剂，对持续存在的细菌具有高度活性，能够在体外强力清除生物膜，并在体内表现出可持续的杀菌效果。ChryA 被认为针对多种关键细胞过程。广泛的遗传和生化方法表明，ChryA 直接与 GlmU 和 DapD 结合，分别参与细胞壁肽聚糖和赖氨酸前体的生物合成途径，并通过与它们共同的底物乙酰辅酶 A 竞争来抑制乙酰转移酶的活性。我们的研究提供了一种有效的抗菌策略，即将多种 MoA 结合到单个小分子上，用于治疗持续性感染。
