Top Anti-Fungal Agents Cause Pathogens to Self-Destruct

Researchers have unveiled a crucial discovery about azole antifungals, the most commonly used class of antifungal agents globally. This breakthrough, led by scientists from the University of Exeter, could significantly enhance strategies to protect both food resources and human health.

Fungal diseases are responsible for the loss of up to 25% of the world's crops annually. In humans, these pathogens can pose severe risks, particularly for individuals with compromised immune systems. Azole fungicides, pivotal in combating these fungal threats, represent a significant portion of the global agricultural fungicide market, valued at over £3 billion annually. These compounds are also essential in treating fatal human fungal infections.

Azoles function by targeting enzymes in the pathogen's cells responsible for producing ergosterol, a cholesterol-like molecule crucial for cellular membranes. By depleting ergosterol, azoles kill the pathogen cells. Despite their widespread use and importance, the precise mechanism by which azoles induce cell death was not well understood until now.

In a study published in Nature Communications, the Exeter research team revealed how azoles lead to the death of pathogenic fungi. Funded by the BBSRC, the investigation focused on the crop pathogenic fungus Zymoseptoria tritici (Z. tritici), known to cause septoria leaf blotch in wheat—a disease with severe economic impact in temperate regions, costing the UK alone over £250 million annually due to decreased harvest and fungicide expenses.

The research employed live-cell imaging and molecular genetics to observe the reaction of Z. tritici cells to azole treatment. Contrary to the previous belief that azoles cause the pathogen cell membrane to perforate, the study found that azoles disrupt ergosterol production, leading to increased mitochondrial activity. This heightened activity generates more toxic by-products, which trigger apoptosis, a "suicide" programme in the pathogen cells. Additionally, reduced ergosterol levels activate macroautophagy, a process where the cell digests its own essential components, including nuclei and organelles.

This dual-pathway of cell death—the initiation of apoptosis and macroautophagy—explains the lethal effect of azoles on fungal pathogens. The researchers extended their findings to rice-blast fungus Magnaporthe oryzae, which devastates rice crops vital for over 3.5 billion people, confirming the same cell death mechanism. They also tested other antifungal drugs like Terbinafine, Tolfonate, and Fluconazole, which similarly induced pathogen cell suicide, indicating a general effect of ergosterol biosynthesis inhibitors.

Lead author Professor Gero Steinberg, a prominent figure in Cell Biology at the University of Exeter, stated that this study challenges the existing understanding of azole fungicides. The findings suggest that azoles push pathogen cells into a "point of no return" after a period of exposure, leading to self-destruction. However, this delayed reaction allows time for pathogens to develop resistance, explaining the increasing azole resistance seen in both crop and human fungal pathogens.

Steinberg emphasized the importance of these insights, hoping they will help optimize control strategies to save lives and ensure food security. The research sheds new light on the functioning of widely-used antifungal agents, potentially paving the way for more effective disease management in agriculture and medicine.

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