Novel way to fight Fungal Infection

 



The goal is to prevent fungus from producing fatty acids, which make up the majority of lipids. As antifungal medication resistance rises, this novel strategy will be especially helpful because it targets a wide variety of fungus species in a novel manner. Cell Chemical Biology, a reputable magazine, published the work.

The majority of us are aware of athlete's foot, a very minor health problem that can be treated at the pharmacy. The Candida, Cryptococcus, and Aspergillus forms of fungi, however, are more dangerous and are responsible for millions of fatalities each year. Similar to bacterial resistance to antibiotics, fungus resistance to drugs is expanding globally, and if nothing is done now, the death toll will probably increase soon.


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There are currently just three main kinds of anti-fungal drugs, and they all function by removing the protective layer that covers fungi. Contrary to popular belief, current treatments are actually quite specific, so even while they all attack the barrier, they may not be effective against all fungus types.

The research team sought a different approach to dangerous fungal control that would work against a variety of species. Their strategy involved screening the structurally varied RIKEN natural product depository (NPDepo) initially against four pathogenic yeasts—three Candida and one Cryptococcus species—that the World Health Organization has designated as important human pathogens. They were searching for a substance that would have an impact on all four species, indicating that it would be effective against a variety of fungi.

After ruling out those that were already known, the researchers were left with three fresh options. The screening revealed many compounds that inhibited fungal growth by at least 50% in each of the four species.

The one of these three that was least hazardous to human cells also inhibited the growth of Aspergillus fumigatus, a very prevalent fungal mold that is fatal to people with impaired immune systems. This substance's RIKEN NPDepo identifier is NPD6433. Finding out what it does was the next step.

The scientists examined how much NPD6433 inhibited development in yeast when the yeast lacked one copy of nearly 1000 distinct genes. They discovered that yeast was more vulnerable to NPD6433 when only one gene—fatty acid synthase—was reduced.

This data indicated that NPD6433 most likely inhibits fatty acid synthase in order to stop the production of fatty acids inside fungus cells. Additional tests revealed the ability of NPD6433 and cerulenin, another fatty acid synthase inhibitor, to eradicate various yeast species in culture.

The Caenorhabditis elegans worm, which was infected with a pathogenic yeast that can cause systemic infection in people after invading through the intestines, was used in the last experiment to examine the effectiveness of NPD6433 treatment. It was decided to adopt C. elegans since its digestive system functions similarly to ours. Tests revealed that administering NPD6433 to sick worms reduced deaths by roughly 50%. This was particularly true for yeast-infected worms that could not be treated with a typical anti-fungal drug.

 

Source 

Iyer, K. R., et al. (2023) Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity. Cell Chemical Biologydoi.org/10.1016/j.chembiol.2023.06.005.


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