Long-term stability of acquired drug resistance and resistance associated mutations in the fungal pathogen Nakaseomyces glabratus (Candida glabrata)
Open accessAbstract
The limited number of available antifungal drugs and the increasing number of fungal isolates that show drug or multidrug resistance pose a serious medical threat. Several yeast pathogens, such as Nakaseomyces glabratus ( Candida glabrata ), show a remarkable ability to develop drug resistance during treatment through the acquisition of genetic mutations. However, how stable this resistance and the underlying mutations are in non-selective conditions remains poorly characterized. The stability of acquired drug resistance has fundamental implications for our understanding of the appearance and spread of drug-resistant outbreaks and for defining efficient strategies to combat them. Here, we used an in vitro evolution approach to assess the stability under optimal growth conditions of resistance phenotypes and resistance-associated mutations that were previously acquired under exposure to antifungals. Our results reveal a remarkable stability of the resistant phenotype and the underlying mutations in a significant number of evolved populations, which conserved their phenotype for at least two months in the absence of drug-selective pressure. We observed a higher stability of anidulafungin resistance over fluconazole resistance, and of resistance-conferring point mutations as compared with aneuploidies. In addition, we detected accumulation of novel mutations in previously altered resistance-associated genes in non-selective conditions, which suggest a possible compensatory role. We conclude that acquired resistance, particularly to anidulafungin, is a long-lasting phenotype, which has important implications for the persistence and propagation of drug-resistant clinical outbreaks.
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Heteroresistance due to environmental stress may remain even after the stress.
“Heteroresistance due to environmental stress may remain even after the stress [134].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [134]
The Results (‘Acquired drug resistance is long-lived in non-selective conditions’; page not provided) show that drug-resistant N. glabratus strains could retain resistance after drug exposure ended. The paper studies acquired drug resistance, however, and does not establish that the persistent phenotype is heteroresistance or that it arose from environmental stress more generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredchrE aneuploidy contributes to heteroresistance after exposing clinical isolates of N. glabrata to anidulafungin.
“Ksiezopolska et al. found chrE aneuploidy contributes to heteroresistance after exposing clinical isolates to anidulafungin [134].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [134]
The Introduction reports that chromosome duplications acquired during fluconazole treatment persisted through subsequent anidulafungin exposure. The Discussion likewise links ChrE aneuploidy to fluconazole resistance and says anidulafungin exposure may stabilize it, not that exposure produced ChrE aneuploidy or that it contributed to heteroresistance in clinical isolates. No passage identified heteroresistance as the measured outcome. (LLM, conf=0.84)
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- Authors
- Ksiezopolska, E., Schikora-Tamarit, M. À., Carlos Nunez-Rodriguez, J., & Gabaldón, T.
- Affiliations
- Barcelona Supercomputing Center (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Gabaldón, Toni
- Venue
- Frontiers in Cellular and Infection Microbiology
- Publisher
- Frontiers Media SA
- Published
- 2024-07-15
- Volume
- 14
- Pages
- 1416509-1416509
- ISSN
- 2235-2988 (ISSN-L)
- PMC
- PMC11284152
- OpenAlex
- W4400664807
- Cited by
- 15
- References
- 53
- Citations by year
- 2026: 10 · 2025: 5
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular and Infection Microbiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UPCommons institutional repository (Universitat Politècnica de Catalunya) (submittedVersion, cc-by-nc-nd)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Gordon and Betty Moore Foundation (GBMF9742)
- European Commission (HORIZON2020, ERC-2016-724173)
- Ministerio de Ciencia e Innovación (PDC2022-133266-I00, PDC2022, PRE2019-088193, CPP2021-008552, PID2021-126067NB-I00, PCI2022-135066-2)
- Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona
- Agència de Gestió d'Ajuts Universitaris i de Recerca (SGR01551)
- Instituto de Salud Carlos III (IMP00019)
- European Regional Development Fund (IMP/00019)
- 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 glabrata, acquired drug resistance, resistance-associated mutations, fluconazole resistance, antifungal resistance, in vitro evolution, aneuploidy, compensatory mutations, pathogenic yeasts
- MeSH terms
- Anidulafungin, Antifungal Agents, Microbial Sensitivity Tests, Mutation, Phenotype, Fluconazole, Drug Resistance, Fungal, Drug Resistance, Multiple, Fungal, Candida glabrata
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