Researchers discover new method to treat fungal infections

TOKYO: Researchers from the RIKEN Centre for Sustainable Research Science (CSRS) and the University of Toronto have identified a novel method for combating fungal infections. The goal is to prevent fungus from producing fatty acids, the primary component of lipids.

Antifungal medication resistance is increasing, and this new technique will be especially valuable because it operates in a novel way and affects a diverse variety of fungal species. The findings of the study were published in the scientific journal Cell Chemical Biology.

Most people have heard of athlete's foot, a relatively minor health problem that may be resolved with a quick trip to the pharmacy. Other fungal infections, however, are more dangerous, and Candida, Cryptococcus, and Aspergillus fungi are responsible for millions of fatalities each year.

Fungal resistance to drugs, like bacterial resistance to antibiotics, is increasing globally, and the mortality toll will undoubtedly climb in the near future unless something is done soon. There are just three primary kinds of antifungal drugs available today, and they all act by breaking the barrier that surrounds fungal cells.

Despite the fact that they all assault the barrier, current therapies are quite specialised, which means that what kills one type of fungus may not kill another.

The group of researchers wanted to find another way to combat harmful fungi, one that would be useful against numerous 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 looked at how much NPD6433 suppressed growth in yeast when the yeast was missing one copy of the gene. They 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.

The final experiment tested how well NPD6433 treatment worked in a live laboratory model organism—the worm Caenorhabditis elegans—which was infected with a pathogenic yeast that can cause systemic infection in humans after invading through the intestines. C. elegans was chosen because it has an intestinal tract that works like ours.

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.

“Drug-resistant fungi are a growing problem, and leads for the development of new drugs offer hope against these evolving pathogens,” says Yoko Yashiroda, lead RIKEN CSRS author of the study. “Our research indicates that targeting fatty acid synthesis is a promising alternative therapeutic strategy for fungal infections, and one which might not require tailor-made solutions for individual species.”