Resistance to echinocandins comes at a cost: The impact of FKS1 hotspot mutations on Candida albicans fitness and virulence
Open accessAbstract
The emergence of Candida strains carrying FKS1 hotspot mutations associated with resistance to echinocandins is cause for concern. However, to assess the potential of such strains to spread within the community and cause lethal infection, the impact of FKS1 mutations on Candida fitness must be determined. We present evidence that C. albicans fks1 mutations carry significant fitness and virulence costs, which are associated with the production of a thickened, chitin-rich cell wall, impaired filamentation and induction of a dampened inflammatory response. If these phenotypic changes remain stable, they can serve as a basis for rational design of strategies to control the spread of echinocandin resistance.
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Selection is anticipated to favour the emergence of compensatory mutations that mitigate the fitness cost of the resistance mutation.
“Given the fitness cost associated with echinocandin resistance due to mutation in the drug target observed in this study, and in others [88], one would anticipate selection to favour the emergence of compensatory mutations that mitigate the fitness cost of the resistance mutation.”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [88]
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Fraser, M. (2019) · UWE Research Repository (UWE Bristol)
Lee, K. K., & Munro, C. A. (2014) · Springer eBooks · doi:10.1007/978-3-662-45782-5_7
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- Authors
- Ben-Ami, R., & Kontoyiannis, D. P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Virulence
- Publisher
- Informa UK Limited
- Published
- 2012-01
- Volume
- 3
- Issue
- 1
- Pages
- 95-97
- ISSN
- 2150-5594 (ISSN-L)
- 2150-5608
- PMC
- PMC3337155
- OpenAlex
- W1992670593
- Cited by
- 39
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 3 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 1 · 2015: 1 · 2014: 8 · 2013: 4 · 2012: 2
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Virulence (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- echinocandin resistance, FKS1 mutations, Candida albicans, fitness cost, filamentation, inflammation, antifungal resistance
- MeSH terms
- Animals, Antifungal Agents, Candida albicans, Candidiasis, Fungal Proteins, Glucosyltransferases, Humans, Mutation, Virulence, Drug Resistance, Fungal, Echinocandins
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