biostudies-literatureJekhmane SNetherlands Centre for One HealthDutch Research Council (NWO)EC | Horizon 2020 Framework ProgrammeEC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)1778-1791https://www.ebi.ac.uk/biostudies/studies/S-EPMC11222147biostudies-literatureUnknown9(7)Antimicrobial resistance is a leading cause of mortality, calling for the development of new antibiotics. The fungal antibiotic plectasin is a eukaryotic host defence peptide that blocks bacterial cell wall synthesis. Here, using a combination of solid-state nuclear magnetic resonance, atomic force microscopy and activity assays, we show that plectasin uses a calcium-sensitive supramolecular killing mechanism. Efficient and selective binding of the target lipid II, a cell wall precursor with an irreplaceable pyrophosphate, is achieved by the oligomerization of plectasin into dense supra-structures that only form on bacterial membranes that comprise lipid II. Oligomerization and target binding of plectasin are interdependent and are enhanced by the coordination of calcium ions to plectasin'Nature microbiologyHost defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism.PMC11222147711.018.001101045485184.035.002184.032.207101008500723.014.003Slingerland CJKunzler MLelli MMatheson EJCochrane RVKLorent JHMedeiros-Silva JCochrane SAJekhmane SCharitou VLavore FConsoli NADerks MGNMaity SRoos WHBreukink EBaldus MWeingarth MFetz CTehrani KHMEAmmerlaan Dvan der Weijde MElenbaas BOWCox RMartin NIfalseHost defence peptide plectasin targets bacterial cell wall precursor lipid II by a calcium-sensitive supramolecular mechanism.Antimicrobial resistance is a leading cause of mortality, calling for the development of new antibiotics. The fungal antibiotic plectasin is a eukaryotic host defence peptide that blocks bacterial cell wall synthesis. Here, using a combination of solid-state nuclear magnetic resonance, atomic force microscopy and activity assays, we show that plectasin uses a calcium-sensitive supramolecular killing mechanism. Efficient and selective binding of the target lipid II, a cell wall precursor with an irreplaceable pyrophosphate, is achieved by the oligomerization of plectasin into dense supra-structures that only form on bacterial membranes that comprise lipid II. Oligomerization and target binding of plectasin are interdependent and are enhanced by the coordination of calcium ions to plectasin'2024-01-01T00:00:00Z2024 Jul2025-04-04T12:55:23.731Z2025-04-04T12:55:23.731ZS-EPMC112221473878302310.1038/s41564-024-01696-9