Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat

Dermcidin encodes the anionic amphiphilic peptide DCD-1L, which displays a broad spectrum of antimicrobial activity under conditions resembling those in human sweat. Here, we have investigated its mode of antimicrobial activity. We found that DCD-1L interacts preferentially with negatively charged bacterial phospholipids with a helix axis that is aligned flat on a lipid bilayer surface. Upon interaction with lipid bilayers DCD-1L forms oligomeric complexes that are stabilized by Zn2+. DCD-1L is able to form ion channels in the bacterial membrane, and we propose that Zn2+-induced self-assembly of DCD-1L upon interaction with bacterial lipid bilayers is a prerequisite for ion channel formation. These data allow us for the first time to propose a molecular model for the antimicrobial mechanism of a naturally processed human anionic peptide that is active under the harsh conditions present in human sweat. The anionic DCD-1L is an antimicrobial peptide active in human sweat. DCD-1L forms cation stabilized oligomeric ion channels. DCD-1L kills bacteria by forming oligomeric ion channels. The anionic antimicrobial peptide DCD-1L is optimally adapted to the conditions in human sweat.