Fungicidal activity of human antimicrobial peptides and their synergistic interaction with common antifungals against multidrug resistant Candida auris

Abstract

Abstract Emergence of Candida auris, a multidrug resistant yeast, demonstrates the urgent need for novel antifungal agents. Human antimicrobial peptides (AMP) are naturally occurring molecules with wide spectrum antimicrobial activity, particularly against a variety of fungi. Therefore, this study examined the antifungal activity of seven different human AMPs against C. auris following the CLSI guidelines. The antifungal activity was further assessed using time kill curve and cell viability assays. For combination interaction, effectiveness of these peptides with three antifungals, fluconazole, amphotericin B and caspofungin, was done following standard protocols. To elucidate the antifungal mechanism, the effects of peptides on membrane permeability was investigated using propidium iodide staining method and confocal imaging. Antifungal susceptibility results showed that all the examined peptides possessed fungicidal effect against C. auris at different levels, with human β-Defensin-3 being the most potent antifungal with MIC values ranging from 3.125–12.5 µg/ml. Time kill curves further confirmed the killing effect of all the tested peptides. Viability assay showed a significant decrease in the percentage of viable cells exposed to different inhibitory and fungicidal concentrations of each peptide (p < 0.01). Furthermore, peptides showed mostly synergistic interaction when combined with conventional antifungal drugs, with caspofungin showing 100% synergy when combined with different AMPs. As antifungal mechanism, peptides disrupted the membrane permeability at concentrations that correlated with the inhibition of growth. Overall, the findings of this study point towards the application of the tested peptides as a monotherapy or as a combination therapy with antifungal drugs to treat multidrug resistant C. auris infections.