Culture samples from a woman’s wound grew Candida auris, a fungus that can cause serious infections in healthcare settings. Genome testing placed the isolate in a clade associated with high levels of antifungal resistance.
In laboratory tests, the strain resisted all four main categories of antifungal drugs. Researchers called it “pan-drug resistant”, or PDR. It was resistant to fluconazole, caspofungin, micafungin, amphotericin B and flucytosine.
The fungus was previously known as Candida auris and is now called Candidozyma auris. The PDR isolate carried mutations in ERG11 and CDR1, genes linked to resistance to azole drugs, as well as an FKS1 mutation associated with echinocandin resistance. It also had a “stop-gain” mutation in FUR1, a gene involved in processing flucytosine.
A separate study in Nature Communications examined Indian clinical isolates to establish how the pathogen defeats two of the three main antifungal classes. The work was led by researchers at the Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, working with collaborators at the Indian Institute of Science Education and Research, Thiruvananthapuram.
The resistance problem was already widespread in those isolates. More than 90 per cent were resistant to common azole-based antifungals such as fluconazole, while about 30 per cent resisted the polyene class.
Azoles and polyenes act on ergosterol, a fat concentrated in the fungal cell membrane. Echinocandins act on the cell wall.
When grown in the presence of fluconazole, C. auris makes extra copies of the Erg1 gene. That increases ergosterol production and cancels the drug’s effect.
Against echinocandins such as caspofungin, the team identified mutations in the Fks1 gene that allow the fungus to resist the medicine. These mutations can allow C. auris to survive caspofungin doses up to 16 micrograms per millilitre.
The genetic changes are not the fungus’s only defence. C. auris without a specific gene mutation or duplication still dies at lower caspofungin concentrations and survives at exceptionally high concentrations. At high doses, caspofungin activates compensatory pathways in the fungus rather than killing it.
One response is a sharp increase in chitin production. Chitin is a raw material of the fungal cell wall, and the fungus uses it to compensate for damage caused by the drug.
The findings establish several routes by which C. auris can withstand medicines designed to target its membrane or cell wall. The emergence of a PDR strain adds a laboratory-confirmed isolate resistant to fluconazole, caspofungin, micafungin, amphotericin B and flucytosine. The brief does not establish why that strain emerged, where it originated, how often it occurs in patients, or which treatments may remain effective.
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