Target-Guided Design and Synthesis of Aryl-Functionalized Promysalin Analogs

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 (IC₅₀ 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.