A synthetic peptide mimic killsCandida albicansand synergistically prevents infection

More than two million people worldwide are affected by life-threatening, invasive fungal infections annually.Candidaspecies are the most common cause of nosocomical, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited. Here we investigate the antifungal mode of action and therapeutic potential of positively charged, synthetic peptide mimics to combat infections byCandida albicans. These synthetic polymers cause stress to the endoplasmic reticulum and affect protein glycosylation, a distinct mode of action compared to currently approved antifungal drugs. The most promising polymer composition caused damage to the mannan layer of the cell wall, with additional membrane-disrupting activity. The synergistic combination of the polymer with caspofungin prevented infection of human epithelial cellsin vitro, improved fungal clearance by human macrophages, and significantly increased host survival in aGalleria mellonellamodel of systemic candidiasis. Additionally, prolonged exposure ofC. albicansto the synergistic combination of polymer and caspofungin did not lead to the evolution of resistant strainsin vitro. Together, this work highlights the enormous potential of these synthetic peptide mimics to be used as novel antifungal formulations as well as adjunctive antifungal therapy.