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In situ captured antibacterial action of membrane-incising peptide lamellae.

Kamal El BattiouiSohini ChakrabortyAndrás F WachaDániel MolnárMayra Quemé-PeñaImola Cs SzigyártóCsenge Lilla SzabóAndrea BodorKata HorvátiGergö GyulaiSzilvia BőszeJudith MihályBálint JezsóLoránd RománszkiJudit TóthZoltán VargaIstván MándityTünde JuhászTamás Beke-Somfai
Published in: Nature communications (2024)
Developing unique mechanisms of action are essential to combat the growing issue of antimicrobial resistance. Supramolecular assemblies combining the improved biostability of non-natural compounds with the complex membrane-attacking mechanisms of natural peptides are promising alternatives to conventional antibiotics. However, for such compounds the direct visual insight on antibacterial action is still lacking. Here we employ a design strategy focusing on an inducible assembly mechanism and utilized electron microscopy (EM) to follow the formation of supramolecular structures of lysine-rich heterochiral β 3 -peptides, termed lamellin-2K and lamellin-3K, triggered by bacterial cell surface lipopolysaccharides. Combined molecular dynamics simulations, EM and bacterial assays confirmed that the phosphate-induced conformational change on these lamellins led to the formation of striped lamellae capable of incising the cell envelope of Gram-negative bacteria thereby exerting antibacterial activity. Our findings also provide a mechanistic link for membrane-targeting agents depicting the antibiotic mechanism derived from the in-situ formation of active supramolecules.
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