Design, synthesis and biological activity of potential retrometabolic polymyxins via thiol-ene chemistry

Despite their nephrotoxicity, polymyxins remain in clinical use as last-resort antibiotics, underscoring the urgent need for alternatives amid rising antimicrobial resistance. We report herein the total chemical synthesis and further biological evaluation of three polymyxin analogues that possess an ester linkage within the heptapeptide ring. Thioether installation was achieved via pre-established vinyl ester formation, permitting a novel intermolecular thiol-ene reaction with a cysteine thiol to form the polymyxin ring. This moiety aims to sensitise the analogue towards esterase enzymes concentrated within the proximal tubule cells of the kidneys, theoretically limiting polymyxin accumulation, mitigating their toxicity.