Synthetic peptidomimetics of antimicrobial peptides (AMPs) are promising antimicrobial drug candidates because they promote membrane disruption and exhibit greater structural and proteolytic stability than natural AMPs. We previously reported selective antifungal 14-helical β-peptides, but the mechanism of antifungal toxicity of β-peptides remains unknown. To provide insight into the mechanism, we studied antifungal β-peptide binding to artificial membranes and living Candida albicans cells. We investigated the ability of β-peptides to interact with and permeate small unilamellar vesicle models of fungal membranes. The partition coefficient supported a pore-mediated mechanism characterized by the existence of a critical β-peptide concentration separating low- and high-partition coefficient regimes. Live cell intracellular tracking of β-peptides showed that β-peptides translocated into the cytoplasm, and then disrupted the nucleus and vacuole sequentially, leading to cell death. This understanding of the mechanisms of antifungal activity will facilitate design and development of peptidomimetic AMPs, including 14-helical β-peptides, for antifungal applications.
Keywords: 14-helical β-peptide; Candida albicans; antifungal β-peptide; intracellular target; mechanism of antifungal peptides; partition coefficients; peptidomimetics; small unilamellar vesicles.
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