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).