Candidacidal mechanism of a Leu/Lys‐rich α‐helical amphipathic model antimicrobial peptide and its diastereomer composed of D , L ‐amino acids

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We investigated the mechanism of candidacidal action of a Lys/Leu-rich α-helical model antimicrobial peptide (K(9)L(8)W) and its diastereomeric peptide (D(9)-K(9)L(8)W) composed of D,L-amino acids. K(9)L(8)W killed completely Candida albicans within 30 min, but D(9)-K(9)L(8)W killed only 72% of C. albicans even after 100 min. Tryptophan fluorescence spectroscopy indicated that the fungal cell selectivity of D(9)-K(9)L(8)W is closely correlated with a selective interaction with the negatively charged PC/PE/PI/ergosterol (5:2.5:2.5:1, w/w/w/w) phospholipids, which mimic the outer leaflet of the plasma membrane of C. albicans. K(9)L(8)W was able to induce almost 100% calcein leakage from PC/PE/PI/ergosterol (5:2.5:2.5:1, w/w/w/w) liposomes at a peptide:lipid molar ratio of 1:16, whereas D(9)-K(9)L(8)W caused only 25% dye leakage even at a peptide:lipid molar ratio of 1:2. Confocal laser-scanning microscopy revealed that FITC-labeled D(9)-K(9)L(8)W penetrated the cell wall and cell membrane and accumulated inside the cells, whereas FITC-labeled K(9)L(8)W did not penetrate but associated with the membranes. Collectively, our results demonstrated that the candidacidal activity of K(9)L(8) W and D(9)-K(9)L(8)W may be due to the transmembrane pore/channel formation or perturbation of the fungal cytoplasmic membranes and the inhibition of intracellular functions, respectively. Finally, D(9)-K(9)L(8)W with potent anti-Candida activity but no hemolytic activity may be potentially a useful lead compound for the development of novel antifungal agents.