Deadly fungus beats antifungal drugs by copying its whole genome

A chance mistake in a laboratory has exposed a startling survival trick used by one of the world’s most dangerous fungal pathogens. Researchers led by the University of Exeter and City St George’s, University of London, have discovered that Candida auris, a deadly yeast that spreads in hospitals, can resist antifungal treatment by making multiple copies of its entire genome. The finding, published in Nature Communications, reveals a previously unknown route through which the fungus adapts to drugs that should kill it, and it could reshape how clinicians approach treatment of this emerging threat.

The discovery was made almost by accident. The team was initially running routine tests for drug resistance when a researcher accidentally left plates of fungal cells incubating for longer than the standard test period. On returning, the researcher found that cells had grown during this extra time, despite being exposed to antifungal drugs. Follow-up testing confirmed something remarkable: rather than relying on the single gene mutations typically associated with drug resistance, the surviving cells had duplicated their whole genome, multiplying the raw material available for mutation and dramatically increasing their odds of stumbling upon a combination of changes that would let them evade the drug.

Candida auris was first described only in 2008, and its origins remain a mystery. In the years since its emergence, outbreaks have been reported on every continent, in more than 60 countries, including the United Kingdom. The World Health Organization has named the fungus a global public health threat and placed it on its critical priority list of fungal pathogens. While rare in the general population, it poses a lethal danger to patients in intensive care units. It clings to patient skin and surrounding medical equipment, spreads readily from person to person, and is notoriously difficult to eradicate from clinical environments.

The stakes are high. Dr Hugh Gifford, clinical lecturer at the University of Exeter’s MRC Centre for Medical Mycology and the study’s first author, who also works as an intensive care physician, described the fungus as a deadly threat to ICU patients. If the infection enters a vulnerable patient’s bloodstream, the death rate reaches 45 per cent. Outbreaks in intensive care units have proved both costly and disruptive: one UK unit had to close and undergo complete refurbishment to stop an outbreak, while another was estimated to have cost one million pounds to control.

Dr Sarah Murphy, formerly a postdoctoral researcher at City St George’s, University of London, and co-first author of the study, explained that the team set out to investigate why antifungal drugs were failing to kill Candida auris even though laboratory tests suggested the fungus was not resistant and the drugs should have worked. When the researchers exposed the fungus to very high concentrations of antifungal agents, they were amazed to find that a tiny population of cells appeared over several days and continued to grow. This persistence pointed to an entirely new survival mechanism, one that had gone undetected because it emerged slowly, over a timescale longer than conventional laboratory testing captures.

What the researchers did not find was equally telling. Gifford noted that the team did not identify any of the DNA mutations that might have been expected. Antifungal drugs target the enzymes that build fungal cell walls, causing the cells to shrivel, explode, or simply stop growing. Yet somehow the surviving cells had endured. The answer lay in their genetics: the cells had made multiple copies of their entire genome. Whole-genome duplication is a trick that other fungi have deployed in the past, but it had not been recognised as a strategy in Candida auris, making the observation a genuine surprise.

The study also revealed a second layer of sophistication. The surviving cells formed two distinct populations, one growing slowly and the other more rapidly, a phenomenon the researchers describe as bet-hedging. By pursuing multiple tactics simultaneously, the fungus maximises its chances of developing resistance and evading treatment. The more rapidly growing cells carried a wide range of mutations in a gene called CRZ1, nicknamed Crazy-one, which is known from studies in other organisms to govern cell wall synthesis. Further tests confirmed the rapid growth of these CRZ1 mutants and showed that their cell walls appeared unaffected by antifungal drugs, effectively neutralising the main weapon in the clinical arsenal.

Senior author Professor Tihana Bicanic, Professor of Infectious Diseases and Mycology at the School of Health and Medical Sciences at City St George’s, University of London, said the findings suggest that fungal infections are more complicated than previously thought, with multiple populations potentially coexisting during an infection. In her view, new and emerging human fungal pathogens such as Candida auris carry what she described as a Swiss Army Knife of innovation within their own genome, enabling stepwise adaptation and drug resistance. She warned that the newly identified mechanism of evolution weakens the antifungal drug arsenal and argued that the results sound the alarm for the urgent development of better antifungal drugs and stronger measures to prevent fungal deaths.

The work, funded primarily by the Medical Research Council with support from the NIHR Biomedical Research Centre in Exeter, is already informing the next stage of the fight against the fungus. The researchers are now exploring the use of antifungal drugs in combination, an approach being pursued through the Exeter-led, UKRI-funded Fungi-CARE programme, run in partnership with colleagues at City St George’s. Combination therapy may deny the fungus the single, predictable pressure that whole-genome duplication so effectively exploits.

The discovery carries broader lessons for microbiology and public health. Conventional susceptibility testing may miss resistance mechanisms that only reveal themselves over extended incubation, meaning patients could be treated with drugs that appear effective in the laboratory but fail at the bedside. Understanding that Candida auris can hedge its bets, deploying whole-genome duplication and mutation of cell wall genes in parallel, gives researchers a clearer picture of what they are up against. As this pathogen continues its spread across hospitals worldwide, uncovering such evolutionary tricks is an essential step toward new treatments and better ways to purge the fungus from the clinical settings where it does the most harm.

Subject of Research: Genome duplication as a mechanism of antifungal drug resistance in Candida auris

Article Title: Unexpected discovery of new mechanism which helps deadly fungus Candida auris evade treatment

Article References: Unexpected discovery of new mechanism which helps deadly fungus Candida auris evade treatment. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: Candida auris, antifungal resistance, genome duplication, CRZ1, cell wall, fungal pathogens, Nature Communications, intensive care, bet-hedging, drug resistance, University of Exeter, mycology