Only four classes of antifungal drugs currently exist, and pathogen resistance to these drugs complicates treatment. A research team has identified resistance mutations in the fungus Candida albicans, the most common cause of fungal infections, for six widely used clinical drugs belonging to the azole class.
In the study, published in the journal Nature Microbiology, the team grouped the mutations and their resistance to the various azoles in a catalog. This can be used by clinical staff to guide them in their choice of treatment.
Camille Bédard, PhD student at the Faculty of Science and Engineering and first author of the study, emphasizes the need to find a suitable antifungal agent quickly, without trial and error.
"The mortality rate can be as high as 70% for immunocompromised people in the case of the C. albicans pathogen. If clinicians know which mutation they’re dealing with, they can look in the catalog to determine the appropriate treatment according to the resistance indicated," reports Camille Bédard, who works under the direction of Christian Landry.
Worrying cross-resistance
For 88% of resistance mutations, protection is effective for several azole drugs at the same time. As the azoles tested all have the same mechanism of action, the team expected to observe this cross-resistance, but not in such proportion. "Azoles act by binding to a key protein in the pathogen’s growth, inhibiting it. When a resistance mutation occurs, the drug can no longer bind to the protein and loses its efficacy", explains the doctoral student. As the molecules are slightly different from one azole to another, she didn’t think there would be such versatile protection.The issue of cross-resistance to azoles concerns Camille Bédard, as this family of antifungals is also used in agriculture. "Certain pathogens present in the environment can be found in humans. This is the case withAspergillus fumigatus, a soil fungus whose spores can be breathed in. In an immunocompromised person, this can cause infections. If the pathogen has already been in contact with an agricultural azole, it could have developed a resistance that also protects it from medical azoles", warns the young researcher, recipient of a 2024 Vanier Scholarship.
In a forthcoming article, she intends to assess the rate of cross-resistance between agricultural and medical azoles for A. fumigatus and other fungi of the same type.
An exhaustive catalog
Rather than selecting mutations that appear to be of interest, the research team is looking at all possible mutations, thus increasing the catalog’s predictive power. "We are able to generate and study mutations that have not yet been observed in nature, and which could emerge in the future. So, even if a mutation is observed in the clinic for the first time, it will be in the catalog and the clinician will be able to know whether or not there is resistance," says Camille Bédard.To study the 4,000 potential mutations, researchers are using a model yeast, baker’s yeast. It is genetically modified to produce the same protein as the C. albicans pathogen targeted by the azole drug. They then test for resistance by putting all the "mutants" in the presence of each antifungal agent. Those that survive are categorized as resistant.
The team now wants 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 catalog for each pathogen?" asks Camille Bédard.
The study was published in the journal Nature Microbiology. Other signatories from Université Laval are Isabelle Gagnon-Arsenault, Jonathan Boisvert, Samuel Plante, Alexandre K. Dubé, Alicia Pageau, Anna Fijarczyk and Christian R Landry. Researchers Jehoshua Sharma, Laetitia Maroc, Rebecca S. Shapiro, of the University of Guelph, also collaborated.
