Azoles activate type I and type II programmed cell death pathways in crop pathogenic fungi

• Published in: Nature communications Vol. 15; no. 1; pp. 4357 - 21
• Main Authors: Schuster, Martin, Kilaru, Sreedhar, Steinberg, Gero
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 14/28; 14/34; 14/35; 14/63; 631/326/193/2542; 631/326/88; Actin; Apoptosis; Apoptosis - drug effects; Ascomycota - drug effects; Ascomycota - metabolism; Ascomycota - pathogenicity; Autophagy - drug effects; Azoles; Azoles - pharmacology; Biosynthesis; Cell activation; Cell death; Cell Membrane - drug effects; Cell Membrane - metabolism; Crops, Agricultural - microbiology; Epoxiconazole; Ergosterol; Ergosterol - biosynthesis; Ergosterol - metabolism; Fluidity; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fungi; Fungicidal activity; Fungicides; Fungicides, Industrial - pharmacology; Heterocyclic compounds; Humanities and Social Sciences; Lethality; Magnaporthe oryzae; Mode of action; Mortality; multidisciplinary; Oryza - metabolism; Oryza - microbiology; Oxygen; Pathogens; Plant Diseases - microbiology; Plant protection; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rice blast; Science; Science (multidisciplinary); Septation; Triazoles - pharmacology; Triticum - microbiology; Zymoseptoria tritici
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48157-9

Triazoles are widely used to control pathogenic fungi. They inhibit the ergosterol biosynthetic pathway, but the precise mechanisms leading to fungicidal activities in many fungal pathogens are poorly understood. Here, we elucidate the mode of action of epoxiconazole and metconazole in the wheat pathogen Zymoseptoria tritici and the rice blast fungus Magnaporthe oryzae . We show that both azoles have fungicidal activity and reduce fluidity, but not integrity, of the plasma membrane. This impairs localisation of Cdc15-like F-BAR proteins, resulting in defective actin ring assembly and incomplete septation. However, mutant studies and pharmacological experiments in vitro and in planta show that azole lethality is due to a combination of reactive oxygen species-induced apoptosis and macroautophagy. Simultaneous inhibition of both programmed cell death pathways abolishes azole-induced cell death. Other classes of ergosterol biosynthesis inhibitors also induce apoptosis and macroautophagy, suggesting that activation of these two cell death pathways is a hallmark of ergosterol synthesis-targeting fungicides. This knowledge will inform future crop protection strategies. Antifungal azoles inhibit ergosterol biosynthesis, but how that leads to fungistatic or fungicidal activities in many pathogenic fungi is poorly understood. Here, Schuster, Kilaru & Steinberg show that azole lethality in the plant pathogens Zymoseptoria tritici and Magnaporthe oryzae is due to a combination of reactive oxygen species-induced apoptosis and macroautophagy.