Synthetic amino acids-based short amphipathic peptides exhibit antifungal activity by targeting cell membrane disruption

Availability of a limited number of antifungal drugs created a necessity to develop new antifungals with distinct mode of action. Investigation on a new series of peptides led us to identify Boc-His-Trp-His[1-(4-tert-butylphenyl)] (10g) as the most promising inhibitor exhibiting IC50 value of 4.4 mu g/mL against Cryptococcus neoformans. Analog 10g exhibit high selectivity to fungal cells and was nonhemolytic and noncytotoxic at its minimum inhibitory concentration. 10g produced fungicidal effect on growing cryptococcal cells and displayed synergistic effect with amphotericin B. Overall cationic character of 10g resulted in interaction with negatively charged fungal membrane while hydrophobicity enhanced penetration inside the cryptococcal cells causing hole(s) formation and disruption to the membrane as evident by the scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy analyses. Flow cytometric investigation revealed rapid death of fungal cells by apopotic pathway.

Automated summary

The limited availability of antifungal drugs has led to the necessity to develop new antifungals with different modes of action. Our investigation on a new series of peptides identified Boc-His-Trp-His[1-(4-tert-butylphenyl)] (10g) as the most promising inhibitor, exhibiting an IC50 value of 4.4 μg/mL against Cryptococcus neoformans. 10g showed high selectivity towards fungal cells and was nonhemolytic and noncytotoxic at its minimum inhibitory concentration. It exerted a fungicidal effect on growing cryptococcal cells and showed synergistic effect with amphotericin B.