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 Biology. doi.org/10.1016/j.chembiol.2023.06.005.
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