Antifungal Host Defense Peptides

Abstract

Fungi infect billions of people every year, yet their contribution to the global burden of disease is largely unrecognized and the repertoire of antifungal agents is rather limited. Thus, treatment of life-threatening invasive fungal infections is still based on drugs discovered several decades ago. In addition, recent data on resistance emergence of fungi emphasize the urgent need for novel antifungal treatments. One alternative strategy is based on host defense peptides. Among the large number of antimicrobial peptides, a group of peptides show primarily antifungal activity by interfering with enzymes of cell wall biosynthesis or specific membrane lipids such as ergosterol. Both are promising targets for antifungal peptides, as they are absent in mammalian cells and hence low toxicity of peptides can be expected. However, most of the antimicrobial peptides exhibit a broad spectrum activity including antifungal activity. These peptides act on the cell membrane level and although their structures vary largely, they share a positive net charge, which facilitates electrostatic interactions with negatively charged lipids of the target cell, and an amphipathic structure, which facilitates incorporation into the cell membrane and in turn membrane disruption. Thereby, membrane lipids differing between mammals and fungi play a central role concerning specificity and efficacy of these peptides. Hence, understanding their molecular mechanism(s) of action will aid in the design of novel antifungal agents. Finally, some of these peptides were shown to act synergistically with conventional drugs, which would further widen the armory to treat especially life-threatening invasive fungal infections.