Structure and mechanism of human antimicrobial peptide dermcidin and its antimicrobial potential

Human beings control viral, bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. This battery of host defense molecules can compromise the integrity of microbial cell membranes and thereby evade various pathways by which bacteria develop rapid antibiotic resistance through mutational adaption. Although more than 2000 antimicrobial peptides (AMPs) from various species have been described and some of which are studied in great detail, the structural and mechanistic basis of their activity remains largely unknown. To understand the mechanisms by which AMPs compromise cell membranes we performed structure biology, electrophysiology and simulations on human dermcidin (DCD) in artificial membranes. Together these techniques reveal the antibiotic mechanism of this fascinating channel structure. The structure of DCD is the first AMP tracked in an oligomeric channel configuration in solution. DCD forms a novel architecture of high-conductance transmembrane channels, composed of zinc-stabilized anion-selective hexameric pores. Molecular dynamics simulations elucidate an unusual membrane permeation pathway for ions and show adjustment of the pore to various membranes by variable tilting angles. Our study comprehensively unravels the mechanism for membrane-disruptive action of this particular mammalian host defense peptide.