Human β-defensin 2 kills Candida albicans through phosphatidylinositol 4,5-bisphosphate-mediated membrane permeabilization

Human defensins belong to a subfamily of the cationic antimicrobial peptides and act as a first line of defense against invading microbes. Their often broad-spectrum antimicrobial and antitumor activities make them attractive for therapeutic development; however, their precise molecular mechanism(s) of action remains to be defined. We show that human β-defensin 2 (HBD-2) permeabilizes Candida albicans cell membranes via a mechanism targeting the plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP₂). We determined the structure of HBD-2 bound to PIP₂, which revealed two distinct PIP₂-binding sites, and showed, using functional assays, that mutations in these sites ablate PIP₂-mediated Fungal growth inhibition by HBD-2. Our study provides the first insight into lipid-mediated human defensin membrane permeabilization at an atomic level and reveals a unique mode of lipid engagement to permeabilize cell membranes.