Structural insights into the interaction of antifungal peptides and ergosterol containing fungal membrane

The treatment of invasive drug-resistant and potentially life-threatening fungal infections is limited to few therapeutic options that are usually associated with severe side effects. The development of new effective antimycotics with a more tolerable side effect profile is therefore of utmost clinical importance. Here, we used a combination of complementary in vitro assays and structural analytical methods to analyze the interaction of the de novo antimicrobial peptide VG16KRKP with the sterol moieties of biological cell membranes. We demonstrate that VG16KRKP disturbs the structural integrity of fungal membranes both invitro and in model membrane system containing ergosterol along with phosphatidylethanolamine lipid and exhibits broad-spectrum antifungal activity. As revealed by systematic structure-function analysis of mutated VG16KRKP analogs, a specific pattern of basic and hydrophobic amino acid side chains in the primary peptide sequence determines the selectivity of VG16KRKP for fungal specific membranes. We have characterized the antifungal properties of the rationally designed antimycotic peptide VG16KRKP, which interacts with ergosterol in fungal membranes but not with the cholesterol moiety present in mammalian membranes. The antifungal activity of VG16KRKP is similar to that of the antimycotic agent amphotericin B. Since VG16KRKP is non-toxic to mammalian cells, it could be an attractive lead compound for the development of effective antifungals with fewer side effects. [Display omitted] •A potent de-novo designed antimicrobial peptide, VG16KRKP, specifically targets fungal membranes over mammalian membranes.•VG16KRKP selectively targets the major sterol component, ergosterol, of the fungal membranes.•VG16KRKP has an immense potential as an effective therapeutic agent against candida keratitis.