Helminth Defense Molecules as Design Templates for Membrane Active Antibiotics

A design template for membrane active antibiotics against microbial and tumor cells is described. The template is an amino acid sequence that combines the properties of helminth defense molecules, which are not cytolytic, with the properties of host-defense peptides, which disrupt microbial membranes. Like helminth defense molecules, the template folds into an amphipathic helix in both mammalian host and microbial phospholipid membranes. Unlike these molecules, the template exhibits antimicrobial and anticancer properties that are comparable to those of antimicrobial and anticancer antibiotics. The selective antibiotic activity of the template builds upon a functional synergy between three distinctive faces of the helix, which is in contrast to two faces of membrane-disrupting amphipathic structures. This synergy enables the template to adapt pore formation mechanisms according to the nature of the target membrane, inducing the lysis of microbial and tumor cells. © 2019 American Chemical Society.