Antifungal Tolerance and Resistance Emerge at Distinct Drug Concentrations and Rely upon Different Aneuploid Chromosomes
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Abstract
Antifungal drug tolerance differs from drug resistance: tolerant cells grow slowly in drug, while resistant cells usually grow well, due to mutations in a few known genes. More than half of Candida albicans clinical isolates have higher tolerance at body temperature than they do at the lower temperatures used for most lab experiments.
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Medium composition regulates miconazole tolerance in a drug-specific manner.
“It seems the medium effect is drug-specific, since previous studies indicate SC5314 is tolerant to ketoconazole but not tolerant to fluconazole on SDC-agar plates at both 30°C and 37°C”
From Miconazole induces aneuploidy-mediated tolerance in Candida albicans that is dependent on Hsp90 and calcineurin (2024) · cites this paper as Yang et al., 2023
The Results section (page unavailable) reports that medium composition affects fluconazole tolerance and that SC5314 is not fluconazole-tolerant on SDC plates at either 30°C or 37°C. It also says earlier work found medium effects on ketoconazole tolerance, but does not establish ketoconazole tolerance on SDC plates at those temperatures. The paper does not address miconazole tolerance, as stated in the supplied claim. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAzole tolerance in Candida is typically temperature-independent and frequently associated with aneuploidy, which may be lost upon temperature changes or ploidy recovery.
“This tolerance is typically temperature-independent and frequently associated with aneuploidy, which may be lost upon temperature changes or ploidy recovery [114,115].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [114]
The Abstract and Discussion report that most clinical C. albicans isolates had temperature-enhanced tolerance, contrary to the claim that tolerance is typically temperature-independent. The Discussion also says these clinical isolates were largely euploid, although experimentally evolved tolerant adaptors commonly acquired aneuploidy. In Results (“Loss of aneuploidy is associated with loss of acquired fluconazole tolerance”; page unavailable), adaptors that became euploid lost their acquired tolerance. Thus, the aneuploidy-and-recovery portion is supported for acquired tolerance, but the broader characterization is not. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTolerance is a non-genetic, whole-populational capacity to survive transient drug exposure, which has been shown to be potentiated at host physiological temperature.
“tolerance, a non‐genetic, whole‐populational capacity to survive transient drug exposure, which has also been shown to be potentiated at host physiological temperature [33].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [33]
The Results section reports that body and febrile temperatures promoted fluconazole tolerance in most of the 133 isolates. But the Introduction says that not all cells in an isogenic tolerant population grow alike, and the Discussion identifies aneuploidy as the primary mechanism of acquired tolerance in the adaptors studied. The paper defines tolerance as slow growth at inhibitory drug concentrations, not whole-population survival after transient exposure. Page numbers were not provided in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAneuploidy has been implicated in antifungal resistance and stress adaptation in related fungal pathogens.
“Given that aneuploidy has been implicated in antifungal resistance and stress adaptation in related fungal pathogens [33, 34, 35]”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [33]
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References 47 · Cited by 62
- Authors
- Yang, F., Scopel, E. F. C., Li, H., Sun, L.-L., Kawar, N., Cao, Y.-B., Jiang, Y.-Y., & Berman, J.
- Affiliations
- Tongji University (CN)
- Shmunis School of Biomedical and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
- Tel Aviv University (IL)
- Department of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Corresponding author
- Berman, Judith
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2023-04-25
- Volume
- 14
- Issue
- 2
- Pages
- e0022723-e0022723
- ISSN
- 2150-7511 (ISSN-L)
- PMC
- PMC10127634
- OpenAlex
- W4323294164
- Cited by
- 62
- References
- 47
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 23 · 2023: 5
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Innovation Program of Shanghai Municipal Education Commission (202101070007E00094)
- EC | ERC | HORIZON EUROPE European Research Council (951475)
- MOST | National Key Research and Development Program of China Stem Cell and Translational Research (2022YFC2303000)
- National Natural Science Foundation of China (82020108032, 81872910)
- Shanghai Key Basic Research Program (19JC1414900)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- antifungal drug tolerance, antifungal resistance, Candida albicans, aneuploidy, drug concentration, body temperature, experimental evolution, point mutations, genetic background
- MeSH terms
- Aneuploidy, Antifungal Agents, Candida albicans, Chromosomes, Drug Tolerance, Microbial Sensitivity Tests, Fluconazole, Mitomycin, Drug Resistance, Fungal
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