Identification and Elimination of Antifungal Tolerance in Candida auris
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Abstract
Antimicrobial resistance is a global health crisis to which pathogenic fungi make a substantial contribution. The human fungal pathogen C. auris is of particular concern due to its rapid spread across the world and its evolution of multidrug resistance. Fluconazole failure in C. auris has been recently attributed to antifungal “tolerance”. Tolerance is a phenomenon whereby a slow-growing subpopulation of tolerant cells, which are genetically identical to susceptible cells, emerges during drug treatment. We use microbroth dilution and disk diffusion assays, together with image analysis, to investigate antifungal tolerance in C. auris to all three classes of antifungal drugs used to treat invasive candidiasis. We find that (1) C. auris is tolerant to several common fungistatic and fungicidal drugs, which in some cases can be detected after 24 h, as well as after 48 h, of antifungal drug exposure; (2) the tolerant phenotype reverts to the susceptible phenotype in C. auris; and (3) combining azole, polyene, and echinocandin antifungal drugs with the adjuvant chloroquine in some cases reduces or eliminates tolerance and resistance in patient-derived C. auris isolates. These results suggest that tolerance contributes to treatment failure in C. auris infections for a broad range of antifungal drugs, and that antifungal adjuvants may improve treatment outcomes for patients infected with antifungal-tolerant or antifungal-resistant fungal pathogens.
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- Authors
- Rasouli Koohi, S., Shankarnarayan, S. A., Galon, C. M., & Charlebois, D. A.
- Affiliations
- Department of Physics, University of Alberta, Edmonton, AB T6G 2R3, Canada
- University of Alberta (CA)
- Corresponding author
- Charlebois, Daniel A.
- Venue
- Biomedicines
- Publisher
- MDPI AG
- Published
- 2023-03-14
- Volume
- 11
- Issue
- 3
- Pages
- 898
- ISSN
- 2227-9059 (ISSN-L)
- PMC
- PMC10045952
- OpenAlex
- W4324357321
- Cited by
- 20
- References
- 53
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 4
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Biomedicines (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Government of Canada’s New Frontiers in Research Fund—Exploration (NFRFE-2019-01208, CFI-40558, RCP-21-008-SEG)
- Canadian Foundation for Innovation’s John R. Evans Leaders Fund (NFRFE-2019-01208, CFI-40558, RCP-21-008-SEG)
- Government of Alberta’s Research Capacity Program (NFRFE-2019-01208, CFI-40558, RCP-21-008-SEG)
- Audrey and Randy Lomnes Early Career Endowment Award (NFRFE-2019-01208, CFI-40558, RCP-21-008-SEG)
- DOST-SEI-UAlberta S&T Graduate Scholarship Program (NFRFE-2019-01208, CFI-40558, RCP-21-008-SEG)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida auris, antifungal tolerance, antifungal resistance, fluconazole, multidrug resistance, invasive candidiasis, azoles, polyenes, echinocandins, chloroquine, adjuvant therapy
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