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.
