New type of treatment beats deadly fungus

Researchers at the RIKEN Center for Sustainable Resources Science (CSRS) and the University of Toronto have discovered a new way to attack fungal infections. The key is to block fungi from being able to make fatty acids, the major component of fats. Resistance to anti-fungal drugs is increasing and this new approach will be particularly useful because it works in a new way and affects a broad range of fungal species.

Their approach was to first screen the structurally-diverse RIKEN natural product depository (NPDepo) against four pathogenic yeasts—three Candida and one Cryptococcus species—which have been identified as critical human pathogens by the World Health Organization. They were looking for something that would affect all four species, which would indicate that it might be effective against a broad range of fungi.

The screening identified several compounds that reduced fungal growth by at least 50% in each of the four species, and after eliminating ones which were already known, the researchers were left with three new possibilities. Among these three, the one least toxic to human cells also reduced growth of Aspergillus fumigatus, an extremely common fungal mold that is deadly to immuno-compromised individuals. The name given to this compound in the RIKEN NPDepo is NPD6433. The next step was to find out what it does.

For almost 1000 different genes, the researchers found that reduction in only one gene, fatty acid synthase, made yeast more susceptible to NPD6433. This result meant that NPD6433 likely works by inhibiting fatty acid synthase and thus prevents fatty acids from being made inside fungal cells. Further experiments showed that NPD6433 and cerulenin, another fatty acid synthase inhibitor, were able to kill numerous yeast species in culture.

Final tests showed that treating infected worms with NPD6433 reduced fatalities by about 50%. Importantly, this was true in worms infected with yeast that were resistant to a standard anti-fungal medication.

Reference: Cell Chemical Biology, DOI 10.1016/j.chembiol.2023.06.005