Researchers have discovered that rocaglate compounds are capable of killing Candida auris. The study, reported this week in mBio, an open-access journal of the American Society for Microbiology, offers hope of finding a treatment for this troubling, emerging pathogen.

“This is the first report of a cell death mechanism in C. auris. This could result in future opportunities to optimize a C. auris specific antifungal compound,” said Kali Iyer, lead study author and a PhD candidate in the Molecular Genetics program at the University of Toronto.

C. auris is an important fungal pathogen for which very few treatment options exist. The first isolates were reported in 2009 in Japan, and since then, the pathogen has been identified on five continents. A key feature of this pathogen is that it seems to be highly resistant to the limited arsenal of antifungal drugs, so there are very few strategies to treat infected patients. C. auris also survives incredibly well on surfaces, so it causes outbreaks in hospitals where it impacts vulnerable, immunocompromised individuals.

To identify novel agents with bioactivity against Candida auris, the researchers screened 2,454 compounds from a diverse collection of molecules. “We screened the entire library looking for molecules that were able to inhibit C. auris growth, and then prioritized those that were the most bioactive or inhibited growth the most,” said Iyer.

The researchers found that C. auris was surprisingly sensitive to translation inhibition by rocaglates, a class of compounds first discovered in mahogany bark that have primarily been investigated as anti-cancer agents. The rocaglates inhibit translation initiation in C. auris, leading to activation of a cell death program that is characterized by features of both apoptosis, a common form of cell death, and autophagy, an alternative mode of cell death. In contrast, the related pathogen Candida albicans showed inherent resistance to the rocaglates, due to an amino acid variant in the drug-binding domain of translation initiation factor 1, the direct target of the compound class.

“Chemical biology screening provides a very powerful platform to identify new molecules that have therapeutic potential and also uncover new vulnerabilities in these fungal pathogens,” said principal study investigator Leah Cowen, PhD, Professor and Chair of Molecular Genetics at the University of Toronto, and co-Director of the CIFAR Fungal Kingdom: Threats & Opportunities program.

Dr. Cowen said there was exciting research stemming from the new findings. “The most direct extension would be to identify ways to further advance this class of molecules as a therapeutic strategy for fungal infections, and to do so, we need to enhance fungal selectivity, because we know that these molecules also inhibit translation initiation in mammalian cells, which we would need to avoid to minimize toxicity to the host,” said Dr. Cowen. “It will be key to selectively target the fungal pathogen and not affect translation initiation in the host.”

In addition, Dr. Cowen said, resistance to the rocaglates can evolve, so researchers need to evaluate the fitness consequences of the resistant mutations and vulnerability to resistance will limit the therapeutic potential of these molecules. She said her research team will continue to screen large collections of diverse molecules for activity against C. auris and other important fungal pathogens that cause life-threatening infectious disease.

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Materials provided by American Society for Microbiology. Note: Content may be edited for style and length.

Journal Reference:

Kali R. Iyer, Luke Whitesell, John A. Porco, Thomas Henkel, Lauren E. Brown, Nicole Robbins, Leah E. Cowen. Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris. mBio, 2020; 11 (2) DOI: 10.1128/mBio.03329-19