New way to attack fungal infections discovered

Researchers at the RIKEN Center for Environmental Sciences (CSRS) and the University of Toronto have discovered a new way to attack fungal infections.

The key is to prevent the fungus from producing fatty acids, the main components of fat. With increasing resistance to antifungal drugs, this new approach is particularly useful because it works in new ways and affects a wide range of fungal species.The research was published in a scientific journal cell chemical biology.

Most of us are familiar with athlete’s foot, but it’s a relatively harmless health problem that can be fixed by visiting the drug store. However, other fungal infections are more serious and Candida, Cryptococcusand Aspergillus Certain fungi are responsible for millions of deaths each year. Similar to bacterial resistance to antibiotics, fungal resistance to drugs is also on the rise worldwide and could lead to an increase in deaths in the near future if action is not taken now.

There are currently only three major classes of antifungal drugs, all of which work by disrupting the barrier surrounding fungal cells. Paradoxically, even if they all attack the barrier, current treatments are actually very specific, and what kills one kind of fungus cannot kill another. means

A group of researchers wanted to find another way to combat harmful fungi, one that works against a large number of species. Their approach was to first screen the structurally diverse RIKEN Natural Products Depot (NPDepo) against he four pathogenic yeasts. Candida and one Cryptococcus Species – Identified as a significant human pathogen by the World Health Organization. They were looking for something that would affect all four species, something that could be effective against a broad spectrum of fungi.

The screen identified several compounds that reduced fungal growth by at least 50% in each of the four species, leaving the researchers with three new possibilities after eliminating known compounds. it was done.

Of these three, the one with the least toxicity to human cells also inhibited cell proliferation. Aspergillus fumigatus, is a very common fungus and fatal to immunocompromised individuals. The name given to this compound at the RIKEN NPDepo is NPD6433. The next step was to find out what it does.

For about 1,000 different genes, the researchers examined how well NPD6433 suppressed yeast growth when the yeast lacked one copy of the gene. They found that only one gene was reduced. fatty acid synthasewhich made the yeast more sensitive to NPD6433.

This result implies that NPD6433 may work by inhibiting. fatty acid synthase Thus, it prevents the production of fatty acids within fungal cells.Further experiments showed that NPD6433 and cerulenin, another fatty acid synthase The inhibitor was able to kill numerous yeast species in culture.

A final experiment tested how effective NPD6433 treatment was in the living laboratory model organism, C. elegans. Caenorhabditis elegans-; it was infected with a pathogenic yeast that can cause systemic infection in humans after entering through the gut. C. Elegance They were chosen because their intestinal tract works just like ours. Testing showed that treating infected worms with her NPD6433 reduced mortality by approximately 50%. Importantly, this was also true for nematodes infected with yeast that were resistant to standard antifungal drugs.

Drug-resistant bacteria have become a serious problem, and new drug development clues offer hope for these evolving pathogens. Our study shows that targeting fatty acid synthesis is a promising alternative therapeutic strategy for fungal infections, which may not require individual species-tailored solutions.. “

Yoko Yashirota, RIKEN CSRS lead author, RIKEN