Role of Lipid Composition in the Antimicrobial Peptide Double Cooperative Effect

The antimicrobial peptide double cooperative effect, where the mixture of two major antimicrobial peptides LL-37 and HNP1 kills bacteria more efficiently while minimizing the host damage by suppressing mammalian cell membrane lysis, has garnered attention due to its potential applications toward efficient and safe antibiotics. However, its mechanism is completely unknown. In this work, we report that the double cooperative effect can be partially recapitulated in synthetic lipid systems just by varying the lipid composition between eukaryotic and <i>Escherichia coli</i> membranes. Although real cell membranes are so much more complex than just lipids, including, e.g., membrane proteins and polysaccharides, our data implicates that one of the main driving forces of the double cooperative effect is a simple lipid-peptide interaction.