In situ captured antibacterial action of membrane-incising peptide lamellae
Kamal el Battioui, Sohini Chakraborty, András Wacha, Dániel Molnár, Mayra Quemé‐Peña, Imola Cs. Szigyártó, Csenge Lilla Szabó, Andrea Bodor, Kata Horváti, Gergő Gyulai, Szilvia Bősze, Judith Mihály, Bálint Jezsó, Loránd Románszki, Judit Tóth, Zoltán Varga, István M. Mándity, Tünde Juhász, Tamás Beke‐Somfai
Abstract
Abstract 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.