Structural Implications of Novel Serine-rich Antimicrobial Peptides Killing Bacteria

Modifying antimicrobial peptides' (AMPs) relative charges and hydrophobicity impacts their self-assembly and interaction with bacterial membranes. We produced novel, rationally designed AMPs utilising amino acids to selectively replace some lysine residues in the widely studied G(IIKK)3I-NH2 (G3) [1]. Using OFFSPEC, we have almost wholly unravelled how replacing lysine residues with serine influences peptide mechanism of action when binding to a model bacterial outer membrane mimic. Neutron reflection reveals serine homologues interact with the bacterial membrane differently depending on serine content, causing either the formation of lipid-peptide nano aggregates on the membrane surface or via direct lipid dissolving and membrane thinning. However, to fully deconstruct the entire interaction, we need to conduct further measurements with a fully deuterated bilayer system, uncovering the peptides' entire mechanism of action.