Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance.
Open accessAbstract
The identification of FKS1 mutations in Candida albicans associated with echinocandin resistance has raised concerns over the spread of drug-resistant strains. We studied the impact of fks1 mutations on C. albicans virulence and fitness. Compared with wild-type strains for FKS1, echinocandin-resistant C. albicans strains with homozygous fks1 hot-spot mutations had reduced maximum catalytic capacity of their glucan synthase complexes and thicker cell walls attributable to increased cell wall chitin content. The fks1 mutants with the highest chitin contents had reduced growth rates and impaired filamentation capacities. Fks1 mutants were hypovirulent in fly and mouse models of candidiasis, and this phenotype correlated with the cell wall chitin content. In addition, we observed reduced fitness of echinocandin-resistant C. albicans in competitive mixed infection models. We conclude that fks1 mutations that confer echinocandin resistance come at fitness and virulence costs, which may limit their epidemiological and clinical impact.
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Echinocandin-resistant Candida isolates have impaired fitness as compared with isogenic FKS wild-type strains.
“Echinocandin-resistant Candida isolates have impaired fitness as compared with isogenic FKS wild-type strains [43,44].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [43]
The F659-DEL in C. glabrata confers resistance to all three echinocandins.
“For example, the F659-DEL in C. glabrata confers resistance to all three echinocandins, whereas the F659S substitution at the same codon gives rise to anidulafungin and caspofungin resistance, whereas the micafungin MIC and in vivo efficacy in a murine animal model remains unchanged (23;25;27–30).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [29]
Mutations at these hot spots have been linked to impaired enzyme capacity, altered cell wall composition (reduced glucan and increased chitin content), increased cell wall thickness, and impaired filamentation properties.
“Thus, mutations at these hot spots have been linked to a) impaired enzyme capacity, b) altered cell wall composition, i.e. reduced glucan and increased chit in content, c) increased cell wall thickness and d) impaired filamentation properties, which contribute to a lower growth rate in vitro and in vivo in drosophila and mouse models (31–33).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [31]
Some laboratories have noted an unexpected high number of C. glabrata and C. krusei isolates being categorised as non-susceptible using the CLSI method for testing caspofungin susceptibility and by using the Etest and Sensititre Yeast One system.
“Despite this, some laboratories have noted an unexpected high number of C. glabrata and C. krusei isolates being categorised as non-susceptible using the CLSI method for testing caspofungin susceptibility and by using the Etest and Sensititre Yeast One system, which are standardised against the CLSI method (29;43–45).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [29]
Resistance mutations often come at a fitness cost.
“Resistance mutations often come at a fitness cost and when that is the case, it may limit the spread of the organism due to competition from wild type isolates when therapy is discontinued.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [31]
These hot spot mutations contribute to a lower growth rate in vitro and in vivo in drosophila and mouse models.
“Thus, mutations at these hot spots have been linked to a) impaired enzyme capacity, b) altered cell wall composition, i.e. reduced glucan and increased chit in content, c) increased cell wall thickness and d) impaired filamentation properties, which contribute to a lower growth rate in vitro and in vivo in drosophila and mouse models (31–33).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [31]
Echinocandin resistance in Candida has been linked to loss of fitness for homozygous Fks1p F641 and S645 mutants of C. albicans and Fks2p S663P mutants of C. glabrata.
“Echinocandin resistance in Candida has been linked to loss of fitness for homozygous Fks1p F641 and S645 mutants of C. albicans and Fks2p S663P mutants of C. glabrata (31–33).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [31]
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- Authors
- Ben-Ami, R., Garcia-Effron, G., Lewis, R. E., Gamarra, S., Leventakos, K., Perlin, D. S., & Kontoyiannis, D. P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Rutgers New Jersey Medical School (US)
- ORCID
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-08-15
- Volume
- 204
- Issue
- 4
- Pages
- 626-635
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- PMC
- PMC3144175
- OpenAlex
- W2109132135
- Cited by
- 162
- References
- 37
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 13 · 2023: 12 · 2022: 9 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 10 · 2017: 9 · 2016: 6 · 2015: 13 · 2014: 13 · 2013: 11 · 2012: 14
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Funders
- National Cancer Institute (CA 016672, P30CA016672)
- National Institute of Allergy and Infectious Diseases (AI069397, R01AI069397)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida albicans, FKS1 mutations, echinocandin resistance, drug resistance, fitness cost, glucan synthase, candidiasis, filamentation, competitive fitness, co-infection
- MeSH terms
- Animals, Antifungal Agents, Candida albicans, Candidiasis, Fungal Proteins, Macrophages, Mutation, Virulence, Gene Expression Regulation, Fungal, Amino Acid Substitution, Drug Resistance, Fungal, Mice, Echinocandins, Genetic Fitness
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