Newswise — Scientists at the RIKEN Center for Sustainable Research Science (CSRS) in collaboration with the University of Toronto have made a groundbreaking discovery in the fight against fungal infections. They have identified a novel method to combat these infections by disrupting the production of fatty acids, a critical component of fats, in fungi. This new approach is particularly significant as it tackles the issue in a unique way and has the potential to impact a wide range of fungal species. Their research, published in the esteemed scientific journal Cell Chemical Biology, marks a crucial step forward in the battle against drug-resistant fungal strains, which have been responsible for severe health problems and millions of deaths worldwide, particularly caused by Candida, Cryptococcus, and Aspergillus types of fungi.

While some fungal infections, like athlete's foot, may seem relatively benign and easily treatable, others pose a more significant threat to public health. The alarming rise of fungal resistance to conventional medications mirrors the concerning pattern seen with bacterial resistance to antibiotics. Unless immediate action is taken, the death toll from these infections is likely to escalate in the near future. Therefore, the innovative approach discovered by the researchers holds great promise for combating this growing global health challenge.

At present, there are only three primary classes of anti-fungal medications available, and their mechanism of action involves targeting the protective barrier surrounding fungal cells. Interestingly, despite their shared focus on disrupting the barrier, these existing treatments exhibit high specificity. This means that while they can effectively eliminate certain fungal species, they may not be equally effective against others. In other words, the medications that prove lethal to one type of fungus may not have the same impact on a different species. This paradox highlights the need for more diverse and comprehensive approaches to combat the various fungal infections.

The team of researchers aimed to discover a more versatile method to combat harmful fungi, one that could effectively target multiple species. To achieve this, they initiated a screening process using the structurally-diverse RIKEN natural product depository (NPDepo) against four pathogenic yeasts. These yeasts included three Candida species and one Cryptococcus species, all recognized as significant human pathogens by the World Health Organization. The researchers sought a substance that would impact all four species, as such an outcome would suggest its potential efficacy against a wide range of fungal infections.

During the screening process, numerous compounds were discovered, which demonstrated the ability to reduce fungal growth by at least 50% in all four targeted species. After eliminating compounds that were already known, the researchers were left with three promising candidates. Among these three, the compound that exhibited the lowest toxicity to human cells also showed efficacy in reducing the growth of Aspergillus fumigatus. This particular fungal mold is highly prevalent and poses a severe threat to individuals with compromised immune systems.

The compound was named NPD6433 in the RIKEN NPDepo. With these encouraging results in hand, the next crucial step for the researchers was to delve into understanding the mechanism of action of NPD6433—what it does and how it exerts its antifungal effects.

The researchers conducted a comprehensive study involving nearly 1000 different genes to investigate the impact of NPD6433 on yeast growth when one copy of each gene was missing. Surprisingly, they observed that the suppression of only one specific gene, fatty acid synthase, rendered the yeast more susceptible to the effects of NPD6433. This finding strongly suggested that NPD6433 functions by inhibiting fatty acid synthase, thereby impeding the synthesis of fatty acids within the fungal cells.

Further experiments were carried out to validate these observations. The researchers tested NPD6433 alongside another fatty acid synthase inhibitor called cerulenin and found that both compounds demonstrated the ability to effectively eliminate numerous yeast species in controlled culture conditions. These results provide compelling evidence that NPD6433 and cerulenin act as potent antifungal agents by targeting fatty acid synthase and disrupting fatty acid production in the fungal cells.

In the final experiment, researchers assessed the effectiveness of NPD6433 treatment using a live laboratory model organism, the worm Caenorhabditis elegans. The worms were infected with a pathogenic yeast capable of causing systemic infection in humans through intestinal invasion. C. elegans was chosen for its similarity to human intestinal tracts. The tests revealed that administering NPD6433 to the infected worms led to a remarkable 50% reduction in fatalities. This outcome held true even in worms infected with yeast strains that exhibited resistance to standard anti-fungal medications.

Yoko Yashiroda, the lead author from RIKEN CSRS, emphasized the significance of this research in addressing the growing problem of drug-resistant fungi. The findings offer hope in the search for new drugs to combat evolving fungal pathogens. Targeting fatty acid synthesis emerged as a promising alternative therapeutic approach for fungal infections—one that potentially eliminates the need for customized solutions tailored to individual fungal species. This discovery represents a substantial step towards the development of effective and broad-spectrum treatments against fungal infections.

Journal Link: Cell Chemical Biology