Azole antifungals inhibit the fungal ergosterol biosynthesis pathway, resulting in either growth inhibition or killing of the pathogen, depending on the species. Here we report that azoles have an initial growth-inhibitory (fungistatic) activity against the pathogen Aspergillus fumigatus that can be separated from the succeeding fungicidal effects. At a later stage, the cell wall salvage system is induced. This correlates with successive cell integrity loss and death of hyphal compartments. Time-lapse fluorescence microscopy reveals excessive synthesis of cell wall carbohydrates at defined spots along the hyphae, leading to formation of membrane invaginations and eventually rupture of the plasma membrane. Inhibition of β-1,3-glucan synthesis reduces the formation of cell wall carbohydrate patches and delays cell integrity failure and fungal death. We propose that azole antifungals exert their fungicidal activity by triggering synthesis of cell wall carbohydrate patches that penetrate the plasma membrane, thereby killing the fungus. The elucidated mechanism may be potentially exploited as a novel approach for azole susceptibility testing.
NCBI PubMed ID: 30082817Publication DOI: 10.1038/s41467-018-05497-7Journal NLM ID: 101528555Publisher: London: Nature Publishing Group
Correspondence: j.wagener
hygiene.uni-wuerzburg.de
Institutions: Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Medizinische Fakultät, LMU München, Munich, Germany, Zell- und Entwicklungsbiologie, Department Biologie II, LMU München, Planegg-Martinsried, Germany, Institut für Hygiene und Mikrobiologie, Julius-Maximilians-Universität Würzburg, Würzburg, Germany, National Reference Center for Invasive Fungal Infections (NRZMyk), Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie, Hans-Knöll-Institut, Jena, Germany, Molecular Microbiology and Biotechnology, Institute of Biology Leiden, Leiden University, Leiden, The Netherlands
Methods: genetic methods, microscopy, fluorescence microscopy
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