Azole-induced cell wall carbohydrate patches kill Aspergillus fumigatus

Bernadette Geißel, Veronika Loiko, Isabel Klugherz, Zhaojun Zhu, Nikola Wagener, Oliver Kurzai, Cees A. M. J. J. Hondel and Johannes Wagener ()
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Bernadette Geißel: Medizinische Fakultät, LMU München
Veronika Loiko: Medizinische Fakultät, LMU München
Isabel Klugherz: Medizinische Fakultät, LMU München
Zhaojun Zhu: Medizinische Fakultät, LMU München
Nikola Wagener: LMU München
Oliver Kurzai: Julius-Maximilians-Universität Würzburg
Cees A. M. J. J. Hondel: Leiden University
Johannes Wagener: Medizinische Fakultät, LMU München

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05497-7

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