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A research team has identified the resistance mutations of the fungus Candida albicans, the most common cause of fungal infections, for six widely used drugs in clinical settings belonging to the azole class.
Candida albicans. Staining: Gram. Microscopy technique: Negative phase contrast. Magnification: 2400x (for an image width of 26 cm, approximately A4 format).
Image Wikimedia
In the study, published in the journal Nature Microbiology, the team compiled the mutations and their resistance to different azoles into a catalog. This can help guide clinical staff in their treatment decisions.
Camille Bédard, a doctoral student at the Faculty of Science and Engineering and the study's first author, emphasizes the need to quickly find a suitable antifungal without trial and error.
"The mortality rate can reach 70% for immunocompromised individuals when infected by the pathogen C. albicans. If clinicians know which mutation they're dealing with, they can consult the catalog to determine the appropriate treatment based on the indicated resistance," says Camille Bédard, who works under the supervision of professor Christian Landry.
Concerning cross-resistance
For 88% of the resistance mutations, the protection is effective for several azole drugs at the same time. Since all the tested azoles share the same mechanism of action, the team expected to observe cross-resistance, but not to such a degree. "Azoles act by binding with a key protein for pathogen growth, which allows them to inhibit it.
When there's a resistance mutation, the drug can no longer bind to the protein and loses its effectiveness," the doctoral student explains. Since the molecules are slightly different from one azole to another, she didn't expect such a broad protective effect.
Camille Bédard is particularly concerned about the issue of cross-resistance to azoles, as this family of antifungals is also used in agriculture. "Some pathogens present in the environment can end up in humans. This is the case with Aspergillus fumigatus, a soil fungus whose spores can be inhaled. In an immunocompromised person, this can cause infections.
If the pathogen has already been exposed to an agricultural azole, it may have developed resistance that also protects it from medical azoles," warns the young researcher, recipient of a 2024 Vanier Scholarship.
In an upcoming article, she plans to assess the rate of cross-resistance between agricultural and medical azoles for A. fumigatus and other similar fungi.
A comprehensive catalog
Rather than selecting mutations of apparent interest, the research team looks at all possible mutations, increasing the catalog's predictive power. "We can generate and study mutations that haven't yet been observed in nature but could emerge in the future. Thus, even if a mutation is observed in a clinic for the first time, it will be in the catalog, and the clinician will know whether or not there's resistance," says Camille Bédard.
To study the 4,000 potential mutations, the researchers use a model yeast, baker's yeast. It is genetically modified to produce the same protein as the pathogen C. albicans, which is targeted by azole drugs. They then test for resistance by exposing all the "mutants" to each antifungal. Those that survive are categorized as resistant.
The team now plans to determine whether the resistance mutations identified for C. albicans will be the same in other pathogenic fungi. "Could we use the catalog for other fungi, or would we need a separate catalog for each pathogen?" wonders Camille Bédard.
The study was published in the journal Nature Microbiology. Other co-authors from Université Laval include Isabelle Gagnon-Arsenault, Jonathan Boisvert, Samuel Plante, Alexandre K. Dubé, Alicia Pageau, Anna Fijarczyk, and Christian R. Landry. Researchers Jehoshua Sharma, Laetitia Maroc, and Rebecca S. Shapiro from the University of Guelph also contributed.