In brief

A whole-genome sequencing study identifies a region of non-coding RNA called DINOR which makes the Candida auris yeast notoriously deadly and difficult to treat.

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Disarming a deadly yeast

23 Jan 2023

Scientists discover a potential therapeutic target to tackle a dangerous drug-resistant yeast strain.

Since the Egyptians used it to bake bread some 5,000 years ago, we’ve had a long relationship with yeast. However, while yeast may be responsible for our favourite beer and bread, not all yeast strains are friendly. Drug-resistant yeast now poses a very real threat to global health.

For example, a species called Candida auris is resistant to up to three classes of antifungal treatments and can withstand harsh decontamination conditions such as high heat and disinfectants. As the species spreads worldwide, it puts vulnerable individuals such as hospitalised patients at risk of serious life-threatening infections.

"C. auris causes hard-to-treat infections with a mortality rate of up to 70 percent,” said Yue Wang from A*STAR. Since its emergence in 2009, the strain has been hard to stop because we don’t understand exactly what makes it tick. “Even today, very few genes have been studied in C. auris, making it difficult to elucidate the molecular mechanisms underlying its multi-drug resistance and stress tolerance,” Wang further explained.

In a bid to answer these questions, Wang teamed up with a research team led by Jianbin Wang from Tsinghua University in Beijing. Together, the scientists examined the entire C. auris genome to look for the specific genes that give the strain its drug-resistant properties.

The team first generated a library of millions of C. auris mutants—each bearing a single gene mutation—and grew the different mutants in a solution containing high concentrations of antifungal drugs. Only the strongest and most drug-resistant mutants survived, allowing the scientists to pinpoint the antifungal resistance genes responsible.

Wang and colleagues discovered that a region of non-coding RNA called DINOR shielded C. auris' DNA from the toxic effects of antifungal drugs. On the other hand, deleting DINOR from the yeast’s genome made it susceptible to treatment. Furthermore, mice infected with DINOR-negative C. auris had much milder disease symptoms compared to those with the unaltered strain.

These results provide critical insights into potential new targets for developing better antifungal therapeutics. However, Wang believes that there are likely other protective genes that assist DINOR in conferring resistance.

“We are keen to identify the interacting partners of DINOR to understand how they work together to govern drug resistance and stress tolerance,” concluded Wang, adding that the team has been awarded a research grant towards achieving this goal.

Since the study in the Institute of Molecular and Cell Biology (IMCB), Wang has joined the A*STAR Infectious Diseases Labs (ID Labs) as a Senior Principal Investigator to continue his work on fungal pathogens.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).

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Gao, J., Chow, E.W.L., Wang, H., Xu, X., Wang, Y. et al. LncRNA DINOR is a virulence factor and global regulator of stress responses in Candida auris, Nature Microbiology 6, (2021). | article

About the Researchers

Yue Wang obtained his PhD from the University of Minnesota in 1988. In 1989, he joined IMCB as a Postdoctoral Research Fellow. He was promoted to Senior Scientist in 1993 to lead a group in the study and utilisation of equatorial microbial diversity to discover novel bioactive compounds. In 2010, he was promoted to Research Director, whose research revolves around studying the human fungal pathogen Candida albicans. On 01 April 2022, he joined A*STAR Infectious Diseases Labs as a Senior Principal Investigator to continue his research on fungal pathogens. For his outstanding research efforts, Wang was awarded the President’s Science Award in 2012.
Jiaxin Gao obtained his PhD from Beijing Normal University. He joined Wang Yue’s lab at IMCB as a Postdoctoral Research Fellow in 2019. Since then, his work has focused on a newly merged fungal pathogen, Candida auris, to provide new insight into fungal pathogenesis and antifungal resistance using functional genomic screens. He received the Excellent Young Scientists Fund Program (Overseas) from the National Natural Science Fund of China in 2022 and will establish his own laboratory at the Institute of Microbiology, Chinese Academy of Sciences in 2023.

This article was made for A*STAR Research by Wildtype Media Group