A synthetic peptide mimic kills Candida albicans and synergistically prevents infection.

Autor: Schaefer S; School of Chemical Engineering, University of New South Wales (UNSW), Sydney, NSW, Australia.; Australian Centre for NanoMedicine, UNSW, Sydney, NSW, Australia.; School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW, Australia.; Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany., Vij R; Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany., Sprague JL; Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany., Austermeier S; Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany., Dinh H; ARC Centre of Excellence in Synthetic Biology, School of Natural Sciences, Macquarie University, North Ryde, NSW, Australia., Judzewitsch PR; School of Chemical Engineering, University of New South Wales (UNSW), Sydney, NSW, Australia.; Australian Centre for NanoMedicine, UNSW, Sydney, NSW, Australia., Müller-Loennies S; Division of Biophysics, Research Center Borstel, Leibniz Lung Center, Borstel, Germany., Lopes Silva T; Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany., Seemann E; Institute of Biochemistry I, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany., Qualmann B; Institute of Biochemistry I, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany., Hertweck C; Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany.; Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany.; Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Jena, Germany., Scherlach K; Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany., Gutsmann T; Division of Biophysics, Research Center Borstel, Leibniz Lung Center, Borstel, Germany.; Centre for Structural Systems Biology (CSSB), Hamburg, Germany., Cain AK; ARC Centre of Excellence in Synthetic Biology, School of Natural Sciences, Macquarie University, North Ryde, NSW, Australia., Corrigan N; School of Chemical Engineering, University of New South Wales (UNSW), Sydney, NSW, Australia.; Australian Centre for NanoMedicine, UNSW, Sydney, NSW, Australia., Gresnigt MS; Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Jena, Germany.; Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany., Boyer C; School of Chemical Engineering, University of New South Wales (UNSW), Sydney, NSW, Australia. cboyer@unsw.edu.au.; Australian Centre for NanoMedicine, UNSW, Sydney, NSW, Australia. cboyer@unsw.edu.au., Lenardon MD; School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW, Australia. m.lenardon@unsw.edu.au., Brunke S; Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany. sascha.brunke@leibniz-hki.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 09; Vol. 15 (1), pp. 6818. Date of Electronic Publication: 2024 Aug 09.
DOI: 10.1038/s41467-024-50491-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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