Cryptococcus neoformans, Unlike Candida albicans, Forms Aneuploid Clones Directly from Uninucleated Cells under Fluconazole Stress
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The gold standard of cryptococcosis treatment consists of induction therapy with amphotericin B followed by lifelong maintenance therapy with fluconazole (FLC). However, prolonged exposure to FLC induces the emergence of clones heteroresistant to azoles. All the heteroresistant clones thus far analyzed have been shown to be aneuploids, but how the aneuploid is formed remains unclear. Aneuploidy in fungi and other eukaryotic cells is known to result most commonly from chromosome missegregation during cell division due to defects in any one of the multiple components and processes that are required for the formation of two genetically identical daughter cells. Although formation of multinucleated cells has been observed in cells exposed to FLC, evidence for the emergence of drug-resistant aneuploid populations directly from such cells has been lacking. We show the evidence that the aneuploid in fluconazole-heteroresistant clones of Cryptococcus neoformans is derived neither from multinucleated cells nor from chromosome missegregation.
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Heteroresistant subpopulations may exist at low frequencies or exhibit resistance only under specific conditions, such as prolonged exposure to antifungal agents or within certain host environments.
“This limitation arises because heteroresistant subpopulations may exist at low frequencies or exhibit resistance only under specific conditions, such as prolonged exposure to antifungal agents or within certain host environments [153,165,167,168].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [167]
The Introduction describes fluconazole-heteroresistant subpopulations as minor, with strain-dependent frequencies below 1% to 10%, and says prolonged fluconazole exposure can lead to resistant populations. It does not establish that resistance appears only in particular host environments; the evidence here concerns C. neoformans and fluconazole, not antifungal agents generally. (LLM, conf=0.86)
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References 27 · Cited by 34
- Authors
- Chang, Y. C., Khanal Lamichhane, A., & Kwon-Chung, K. J.
- Affiliations
- National Institutes of Health (US)
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Corresponding author
- Kwon-Chung, Kyung J.
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2018-12-21
- Volume
- 9
- Issue
- 6
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC6282203
- OpenAlex
- W2902577803
- Cited by
- 34
- References
- 27
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 4 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 1 · 2019: 5
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- HHS | NIH | NIH Office of the Director
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Cryptococcus neoformans, fluconazole, aneuploidy, heteroresistance, azole resistance, multinucleated cells, chromosome missegregation, Candida albicans, antifungal resistance, clonal evolution
- MeSH terms
- Structural Maintenance of Chromosome Protein 1, Aneuploidy, Antifungal Agents, Candida albicans, Chromosomal Proteins, Non-Histone, Cryptococcus neoformans, Mitosis, Fluconazole, Cell Cycle Proteins, Chromosome Segregation, Drug Resistance, Fungal, Time-Lapse Imaging
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