Golden Martina M, Brzezinski Carter U, Wuest William M
Department of Chemistry, Emory University, Atlanta, GA, 30322, USA.
Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Chembiochem. 2025 May 27;26(10):e202401030. doi: 10.1002/cbic.202401030. Epub 2025 Apr 4.
The development of new narrow-spectrum antibiotics is a promising approach to combat antibiotic resistance. Promysalin, a secondary metabolite isolated from Pseudomonas putida, exhibits potent species-specific inhibition of the pathogen P. aeruginosa (IC 21 nM). Herein, the total synthesis and stereochemical assignment of promysalin, structure-activity relationship studies, and the identification of its molecular target, succinate dehydrogenase, are previously reported by the group. These findings enable computational studies of promysalin's interactions with succinate dehydrogenase, revealing a novel binding site region primed for π-π stacking interactions with a nearby tryptophan residue. It is hypothesized that new aromatic analogs of promysalin can target this beneficial interaction, potentially leading to more potent inhibitors of P. aeruginosa growth. Herein, the in silico design of these analogs, a scalable and general synthetic route to access them, and characterization of their activity against a panel of clinically relevant P. aeruginosa strains are reported.
开发新型窄谱抗生素是对抗抗生素耐药性的一种有前景的方法。普罗米萨林是从恶臭假单胞菌中分离出的一种次级代谢产物，对病原体铜绿假单胞菌表现出强大的种属特异性抑制作用（IC 21 nM）。该研究小组此前已报道了普罗米萨林的全合成、立体化学归属、构效关系研究以及其分子靶点琥珀酸脱氢酶的鉴定。这些发现使得能够对普罗米萨林与琥珀酸脱氢酶的相互作用进行计算研究，揭示了一个新的结合位点区域，该区域准备好与附近的色氨酸残基进行π-π堆积相互作用。据推测，普罗米萨林的新型芳香族类似物可以靶向这种有益的相互作用，有可能产生更有效的铜绿假单胞菌生长抑制剂。本文报道了这些类似物的计算机辅助设计、一种可扩展且通用的合成路线以获取它们，以及它们对一组临床相关铜绿假单胞菌菌株的活性表征。
