A synthetic peptide mimic kills Candida albicans and synergistically prevents infection

• Published in: Nature communications Vol. 15; no. 1; pp. 6818 - 22
• Main Authors: Schaefer, Sebastian, Vij, Raghav, Sprague, Jakob L., Austermeier, Sophie, Dinh, Hue, Judzewitsch, Peter R., Müller-Loennies, Sven, Lopes Silva, Taynara, Seemann, Eric, Qualmann, Britta, Hertweck, Christian, Scherlach, Kirstin, Gutsmann, Thomas, Cain, Amy K., Corrigan, Nathaniel, Gresnigt, Mark S., Boyer, Cyrille, Lenardon, Megan D., Brunke, Sascha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-08-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14; 14/28; 14/63; 45; 45/23; 45/61; 631/154/556; 631/326/22/1292; 631/92/555; Addition polymerization; Animals; Antifungal activity; Antifungal Agents - pharmacology; Candida albicans; Candida albicans - drug effects; Candidiasis; Candidiasis - drug therapy; Candidiasis - microbiology; Caspofungin; Caspofungin - pharmacology; Cell Wall - drug effects; Cell walls; Damage tolerance; Defensins; Drug development; Drug resistance; Drug Synergism; Drugs; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - microbiology; Epithelium; Fungal infections; Fungi; Fungicides; Glycosylation; Humanities and Social Sciences; Humans; Invasive species; Macrophages; Macrophages - drug effects; Macrophages - microbiology; Mannan; Mannans - chemistry; Mannans - pharmacology; Microbial Sensitivity Tests; Mode of action; Mortality; Moths - drug effects; Moths - microbiology; multidisciplinary; Nosocomial infection; Peptides; Peptides - chemistry; Peptides - pharmacology; Pharmaceuticals; Polymers; Polymers - chemistry; Polymers - pharmacology; Protein composition; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50491-x

More than two million people worldwide are affected by life-threatening, invasive fungal infections annually.
Candida
species are the most common cause of nosocomial, 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
Candida albicans
infections. Our data indicates that these synthetic polymers cause endoplasmic reticulum stress and affect protein glycosylation, a mode of action distinct from currently approved antifungal drugs. The most promising polymer composition damaged 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 cells in vitro, improved fungal clearance by human macrophages, and significantly increased host survival in a
Galleria mellonella
model of systemic candidiasis. Additionally, prolonged exposure of
C.

albicans
to the synergistic combination of polymer and caspofungin did not lead to the evolution of tolerant strains in 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.
Fungal infections are severely underestimated as a cause of mortality, and alternative drugs are urgently needed. Here, Schaefer et al. show that a synthetic polymer mimicking defensins shows different, but synergistic activity with known antifungals.