biostudies-literatureUnknownNa TUA chemodiverse library of new semi-synthetic antimicrobial peptides is reported herein. The polymyxin B nonapeptide (PMBN) holds promise as a developmental platform to access potent antimicrobial lipopeptide derivatives that circumvent the serious side effects of natural polymyxins used in clinical settings. By combining our unique radical thiol-ene lipidation strategy (CLipPA) with a chemoenzymatic synthesis, we achieved the chemoselective re-functionalisation of semi-synthetic PMBN, affording a family of potent "soft drugs" decorated with linear, cyclo- and branched alkyl and aromatic esters of varying steric properties. The high efficiency of this late-stage diversification strategy is demonstrated for lipopeptide semi-synthesis. In this process, the significance of the lipid orientatioRSC medicinal chemistryhttps://www.ebi.ac.uk/biostudies/studies/S-EPMC12907753biostudies-literatureIntroducing CLipPA lipid chemodiversity to enzymatically truncated polymyxin B: a soft drug strategy to combat Gram-negative pathogens.PMC12907753Siow AGoggin BLAllison JRSander VCook GMDaysh ZFerguson SABrimble MAOwen JGPainter GFCampbell GHanna CCNa TUHermant YOHarris PWRCameron AJChan STSDavidson AJfalseIntroducing CLipPA lipid chemodiversity to enzymatically truncated polymyxin B: a soft drug strategy to combat Gram-negative pathogens.A chemodiverse library of new semi-synthetic antimicrobial peptides is reported herein. The polymyxin B nonapeptide (PMBN) holds promise as a developmental platform to access potent antimicrobial lipopeptide derivatives that circumvent the serious side effects of natural polymyxins used in clinical settings. By combining our unique radical thiol-ene lipidation strategy (CLipPA) with a chemoenzymatic synthesis, we achieved the chemoselective re-functionalisation of semi-synthetic PMBN, affording a family of potent "soft drugs" decorated with linear, cyclo- and branched alkyl and aromatic esters of varying steric properties. The high efficiency of this late-stage diversification strategy is demonstrated for lipopeptide semi-synthesis. In this process, the significance of the lipid orientatio2026-01-01T00:00:00Z2026 Feb2026-07-16T05:05:21.48Z2026-07-09T10:38:05.67ZS-EPMC129077534170512710.1039/d5md01141h