Identification and Elimination of Antifungal Tolerance in Candida auris

• Published in: Biomedicines Vol. 11; no. 3; p. 898
• Main Authors: Rasouli Koohi, Samira, Shankarnarayan, Shamanth A, Galon, Clare Maristela, Charlebois, Daniel A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14-03-2023; MDPI
• Subjects: adjuvant; Adjuvants; Antifungal agents; antifungal tolerance/resistance; Antimicrobial agents; Antimicrobial resistance; broth microdilution assay; Candida auris; Candidiasis; Chloroquine; disk diffusion assay; diskImageR; Drugs; Echinocandins; Fluconazole; Fungal infections; Fungi; Image processing; Laboratories; Multidrug resistance; Pathogens; Phenotypes; Public health; Ribosomal DNA; Tropical diseases; Canada; Candida auris; adjuvant; diskImageR; human fungal pathogen; broth microdilution assay; antifungal tolerance/resistance; disk diffusion assay
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11030898

Antimicrobial resistance is a global health crisis to which pathogenic fungi make a substantial contribution. The human fungal pathogen
is of particular concern due to its rapid spread across the world and its evolution of multidrug resistance. Fluconazole failure in
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
to all three classes of antifungal drugs used to treat invasive candidiasis. We find that (1)
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
; 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
isolates. These results suggest that tolerance contributes to treatment failure in
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.