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Understanding The Logic Of Azoles Self-Destruction In Fungal Pathogens

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Groundbreaking work conducted by the University of Exeter has determined that azole antifungals catalyze autodestruction in fungal pathogens by suppressing ergosterol synthesis, a revelation that assists in thwarting fungal resistance and ensures the safety of food and health.

Researchers deduce that antifungals, specifically the azoles which are dominantly employed worldwide, prompt self-annihilation in pathogens. This investigation, spearheaded by the University of Exeter, holds the potential to improve tactics in safeguarding food security and public health.

Fungal contagions contribute to a roughly 25% decrease in worldwide crop yields. They also pose significant challenges to human health, especially threatening for individuals with weakened immune systems.

Significance of Azole Fungicides

The most vital defense against plant diseases caused by fungi is represented by azole fungicides. With these fungicidal agents accounting for 25% of the global agricultural fungicide market and yielding a worth of over £3 billion (~$3.8 billion) each year, their importance in managing plant fungus is evident. Moreover, antifungal azoles also play a critical role in combating life-threatening fungi in humans, which underscores their utility in fungal disease management.

These fungicides act on pathogen cells by targeting specific enzymes responsible for producing ergosterol, a molecule akin to cholesterol and a crucial component of cell membranes. The interference with ergosterol synthesis by azoles leads to the destruction of pathogen cells. However, the precise mechanics behind this destruction were not fully understood until now.

Fresh Perspectives from the University of Exeter

In an innovative study issued on this date (May 31) in Nature Communications, scholars from the University of Exeter divulge the cell death mechanisms associated with azole application in harmful fungi.

With BBSRC funding, the investigative collective, directed by Professor Gero Steinberg, utilized a fusion of live-cell imaging and molecular genetics to elucidate why blocking ergosterol production culminates in cell death within the crop-damaging fungus Zymoseptoria tritic (Z. tritici). This particular fungus is responsible for the condition known as septoria leaf blotch in wheat, a significant ailment in temperate regions causing over £250 million in annual damages in the UK, stemming from crop losses and fungicide application costs.

Processes of Azole-Induced Cellular Death

The team from Exeter watched Z. tritici cells in vivo, subjected them to agricultural azoles, and scrutinized their response at the cellular level. Contrary to the established presumption that azoles eradicate pathogen cells by puncturing the cellular membrane, the researchers discovered that the actual mechanism is different. They showed that the diminishing levels of ergosterol instigated by azoles bolster the activity of the cell’s mitochondria, labeled as the cell’s “powerhouse,” essential for generating the “fuel” that underpins metabolic activities in the pathogen cell. Extra production of “fuel” is typically benign, yet this process also yields more harmful by-products. These damaging by-products activate a “suicide” agenda within the cells, known as apoptosis. Additionally, the shortage of ergosterol also sparks another self-destructive sequence, compelling the cell to digest its own essential organelles, such as nuclei, a phenomenon labeled as macroautophagy (depicted in Figure 1). The authors conclude that these cell death pathways are critical to the efficacy of azoles. They suggest that azoles coerce the fungal pathogen into “suicide” by setting off these self-destructive reactions.

Wider Consequences and Prospective Avenues

Further examination revealed a similar mechanism of azole-induced cell termination in the rice-blast fungus Magnaporthe oryzae, a disease agent which can devastate up to 30 percent of rice, an elemental staple food for over 3.5 billion individuals worldwide. Additional antifungal agents targeting ergosterol synthesis pathways, such as Terbinafine, Tolfonate, and Fluconazole, were tested and found to elicit identical cellular responses, implying that cellular suicide is a typical outcome of ergosterol biosynthesis inhibition.

Lead author Professor Gero Steinberg, who possesses the Cell Biology Chair and directs the Bioimaging Centre at the University of Exeter, remarked: “Our results revolutionize the prevailing understanding of the mechanisms through which azoles exterminate fungal pathogens. We’ve established that azoles incite cellular “suicide” schemes, culminating in pathogen self-demolition. This cellular reaction surfaces after a pair of days following azole treatment, indicating that cells reach a ‘point of no return’ after a certain period exposed to the drugs. Regrettably, this delay permits the pathogen sufficient time to cultivate resistance to azoles, elucidating why fungal pathogens are increasingly escaping azole’s lethal effects, reducing their efficacy against diseases in both crops and humans.

“Our investigations shine a spotlight on the action of these paramount fungicidal agents against crop and human pathogens globally. We are hopeful that our findings will benefit the optimization of control strategies that could potentially save lives and bolster food security for the years ahead,” he added.

Image Source: Unsplash

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