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Azole-induced cell wall carbohydrate patches kill Aspergillus fumigatus
Bernadette Geißel1, Veronika Loiko1, Isabel Klugherz1
1Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Medizinische Fakultät, LMU München, Pettenkoferstraße 9a, 80336, Munich, Germany.
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.
Insights
Azole antifungals initially inhibit Aspergillus fumigatus growth. Later, they trigger cell wall changes causing membrane damage and fungal death, a mechanism useful for susceptibility testing.
Area of Science:
- Medical Mycology
- Molecular Biology
- Antifungal Drug Action
Background:
- Azole antifungals target fungal ergosterol biosynthesis, causing growth inhibition or death.
- Aspergillus fumigatus is a significant fungal pathogen.
- The precise fungicidal mechanism of azoles against A. fumigatus requires further elucidation.
Purpose of the Study:
- To delineate the fungistatic versus fungicidal mechanisms of azoles against Aspergillus fumigatus.
- To investigate the role of the cell wall salvage system in azole-induced fungal death.
- To explore potential applications in azole susceptibility testing.
Main Methods:
- Time-lapse fluorescence microscopy to observe fungal cell dynamics.
- Assays to monitor fungal growth inhibition and cell death.
- Inhibition of β-1,3-glucan synthesis to assess its role in azole toxicity.
Main Results:
- Azoles exhibit distinct fungistatic and fungicidal phases against A. fumigatus.
- Fungicidal effects involve the induction of the cell wall salvage system, leading to cell integrity loss.
- Excessive cell wall carbohydrate synthesis causes plasma membrane invaginations and rupture.
- Inhibiting β-1,3-glucan synthesis delays fungal death.
Conclusions:
- Azole fungicidal activity is mediated by triggering cell wall carbohydrate patch synthesis that damages the plasma membrane.
- This mechanism of fungal death offers a novel target for azole susceptibility testing.
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