Scientists have discovered an innovative way to battle fungal infections by inhibiting the production of fatty acids in fungi. The newly identified compound, NPD6433, has demonstrated its efficacy across various fungi, offering a beacon of hope amid growing global drug resistance.
The RIKEN Center for Sustainable Research Science (CSRS) and the University of Toronto have revealed a unique method to fight against fungal infections. This technique centers on hindering the fungi’s capacity to generate fatty acids, essential components of fats. As resistance to anti-fungal medications continues to grow, this fresh approach, distinct and effective against an extensive array of fungal species, could be especially advantageous. The research was published in the scientific periodical, Cell Chemical Biology.
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The Escalating Danger of Fungal Infections
Most individuals recognize conditions like athlete’s foot, a minor health problem easily treatable at the local pharmacy. However, infections caused by fungi such as Candida, Cryptococcus, and Aspergillus are far graver. These fungi are accountable for millions of fatalities annually. Similar to the rising resistance to antibiotics, the global opposition to anti-fungal treatments is also growing. Therefore, without timely intervention, the mortality rate is anticipated to climb in the coming years.
At the moment, there are only three primary classes of anti-fungal medications available, all designed to break down the fungal cell barrier. Interestingly, although they all focus on the cell barrier, they exhibit a surprising species-specificity. This means a drug efficient against one type of fungus may be ineffective against another.
Pursuing Wide-Ranging Anti-Fungal Answers
The research team looked for an alternative strategy to counteract detrimental fungi, one capable of targeting various species. Their initial step was to examine the structurally varied RIKEN natural product depository (NPDepo) against four pathogenic yeasts, including three Candida and one Cryptococcus species, designated as vital human pathogens by the WHO. Their objective was to identify an agent with an effect on all four species, indicating potential effectiveness against diverse fungi.
The screening unveiled several compounds that lessened fungal growth by a minimum of 50% in each species. After discarding known substances, three new possibilities were identified. Among these, the least harmful to human cells also restricted the growth of Aspergillus fumigatus, a common and fatal fungal mold for those with weakened immune systems. This substance, NPD6433, then went through additional scrutiny to define its action mode.
Exploring the Action of NPD6433
The scientists studied how NPD6433 inhibited growth in yeast for almost a thousand genes, when the yeast was deficient in one copy of the gene. They found that only the reduction of the fatty acid synthase gene increased the yeast’s vulnerability to NPD6433. This suggested that NPD6433 likely operates by curbing fatty acid synthase, blocking the creation of fatty acids inside fungal cells. Follow-up experiments illustrated that NPD6433 and cerulenin, another fatty acid synthase inhibitor, could kill various yeast species in culture.
In a concluding experiment, NPD6433’s effectiveness was assessed in a live laboratory model organism—the worm Caenorhabditis elegans—infected with a yeast capable of causing human systemic infection. Tests indicated that NPD6433 treatment diminished deaths by roughly 50%, even in worms infected with yeast resistant to conventional anti-fungal medication.
“Rising drug-resistant fungi present an escalating challenge, and the discovery of potential new drug leads provides optimism in combating these progressively adaptive pathogens,” states Yoko Yashiroda, the primary RIKEN CSRS researcher of the study. “Our findings show that targeting fatty acid synthesis is a hopeful alternative approach for treating fungal infections, without the necessity for individualized solutions for each species.”
Reference: “Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity” by Kali R. Iyer, Sheena C. Li, Nicole M. Revie, Jennifer W. Lou, Dustin Duncan, Sara Fallah, Hiram Sanchez, Iwona Skulska, Mojca Mattiazzi Ušaj, Hamid Safizadeh, Brett Larsen, Cassandra Wong, Ahmed Aman, Taira Kiyota, Mami Yoshimura, Hiromi Kimura, Hiroyuki Hirano, Minoru Yoshida, Hiroyuki Osada, Anne-Claude Gingras, David R. Andes, Rebecca S. Shapiro, Nicole Robbins, Mohammad T. Mazhab-Jafari, Luke Whitesell, Yoko Yashiroda, Charles Boone, and Leah E. Cowen, 26 June 2023, Cell Chemical Biology.
DOI: 10.1016/j.chembiol.2023.06.005
Frequently Asked Questions (FAQs) about fokus keyword: NPD6433
What is the new compound NPD6433, and how does it combat fungal infections?
NPD6433 is a novel compound discovered by researchers at the RIKEN Center for Sustainable Research Science (CSRS) and the University of Toronto. It works by inhibiting the production of fatty acids within fungal cells, a key component of fats. By blocking this function, NPD6433 has shown effectiveness across various fungi, offering a new approach to combating fungal infections amid rising global drug resistance.
What types of fungi could be affected by this compound?
The compound NPD6433 has demonstrated efficacy against a broad spectrum of fungi, including pathogenic yeasts like Candida and Cryptococcus species, and Aspergillus fumigatus, a prevalent and deadly fungal mold. It suggests a potential wide-ranging impact against diverse fungi.
Why is this discovery significant in the face of growing drug resistance?
With global resistance to anti-fungal medications on the rise, current treatments may become less effective. NPD6433 offers a unique approach, targeting fatty acid synthesis within fungal cells, making it a promising alternative therapeutic strategy. Its ability to combat fungi resistant to standard anti-fungal medication makes it particularly valuable.
How was the effectiveness of NPD6433 tested?
The effectiveness of NPD6433 was tested through several experiments, including screening against four pathogenic yeasts, assessing its impact on nearly 1000 different genes in yeast, and experimenting with a live laboratory model organism, the worm Caenorhabditis elegans. These tests revealed its ability to inhibit growth and decrease fatalities in infected organisms.
Is targeting fatty acid synthesis in fungi a common approach?
No, targeting fatty acid synthesis is a novel approach to treating fungal infections. Unlike the three primary classes of existing anti-fungal medications that focus on breaking down the fungal cell barrier, NPD6433 works by inhibiting fatty acid synthase, preventing the synthesis of fatty acids within fungal cells. This unique mechanism offers a new way to fight against a broad range of fungal species.
