Fungal diseases are responsible for the loss of up to 25% of the world’s crops and also pose a risk to humans, especially those with weakened immune systems.
The study, led by the University of Exeter, found that the most commonly used class of antifungals can cause pathogens to self-destruct. This discovery has significant implications for improving methods of protecting both food security and human lives.
Azole fungicides are the most effective defense against fungal plant diseases and make up a significant portion of the global agricultural fungicide market, valued at over £3 billion annually. These antifungal chemicals are also crucial in treating pathogenic fungi that pose a serious threat to human health. Azoles work by targeting enzymes in the pathogen cell responsible for producing ergosterol, a cholesterol-like molecule crucial for cellular bio-membranes. By depleting ergosterol, azoles effectively kill the pathogen cells.Despite their importance, little is known about the actual cause of pathogen death when it comes to azoles. A new study published in Nature Communications by University of Exeter scientists has revealed the cellular mechanism by which azoles kill pathogenic fungi. Professor Gero Steinberg and his team, funded by the BBSRC, used live-cell imaging approaches and molecular genetics to understand why the inhibition of ergosterol synthesis leads to cell death in the crop pathogenic fungus Zymoseptoria tritic (Z. tritici), which causes septoria leaf blotch in wheat, a serious disease.In moderate climates, it is estimated that in the UK alone, more than £250 million per year is spent on costs related to harvest loss and fungicide spraying due to Zymoseptoria tritici (Z. tritici).
The team from Exeter observed living Z. tritici cells, treated them with agricultural azoles, and examined the cellular response. They discovered that the previously accepted concept that azoles kill the pathogen cell by causing perforation of the outer cell membrane is not accurate. Instead, they found that azole-induced reduction of ergosterol increases the activity of cellular mitochondria, which is the “powerhouse” of the cell, necessary to produce the cellular “fuel” that drives all metabolic processes.In the cell of the pathogen, producing more “fuel” is not harmful on its own. However, this process leads to the creation of more toxic by-products. These by-products start a “suicide” program in the pathogen cell called apoptosis. Additionally, lower levels of ergosterol also activate a second “self-destruct” pathway, causing the cell to consume its own nuclei and other essential organelles in a process known as macroautophagy. The researchers demonstrate that both of these pathways contribute to the deadly effects of azoles. They conclude that azoles induce the fungal pathogen to undergo “suicide” by triggering self-destruction.
The researchers discovered the same mechanismMechanism of how azoles kill pathogen cells in rice-blast fungus Magnaporthe oryzae. This fungus causes a disease that can kill up to 30% of rice, which is an important food crop for over 3.5 billion people worldwide. The researchers also tested other anti-fungal drugs that target ergosterol biosynthesis, such as Terbinafine, Tolfonate, and Fluconazole. These drugs all resulted in similar responses in the pathogen cells, indicating that cell suicide is a common result of ergosterol biosynthesis inhibitors.
Lead author Professor Gero Steinberg, who is a Cell Biology Chair and Director of the Bioimaging CA researcher at the University of Exeter stated that the discovery changes our understanding of how azoles eliminate fungal pathogens. The study reveals that azoles activate cellular “suicide” processes, leading to the destruction of the pathogen. This cellular response occurs after two days of treatment, indicating that cells reach a critical point after being exposed to azoles for some time. Unfortunately, this allows the pathogen to develop resistance to azoles, leading to the advancement of azole resistance in fungal pathogens. This ultimately increases the likelihood of failure to combat the disease in crops and humans. The research provides insight into the activity of azoles and the development of resistance in fungal pathogens.One of the most commonly used chemical control agents in crop and human pathogens worldwide. The hope is that the results will be helpful in improving control strategies to save lives and ensure food security in the future.”
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