Low Prevalence of fks1 Hot Spot 1 Mutations in a Worldwide Collection of Candida Strains

Castanheira, Mariana; Woosley, Leah N.; Diekema, Daniel J.; Messer, Shawn A.; Jones, Ronald N.; Pfaller, Michael A.

doi:10.1128/aac.01711-09

Cited by 126Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal and yeast genetics research

Low Prevalence of fks1 Hot Spot 1 Mutations in a Worldwide Collection of Candida Strains

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Castanheira, Mariana, Woosley, Leah N., Diekema, Daniel J., Messer, Shawn A., Jones, Ronald N., Pfaller, Michael A.·2010·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.01711-09PMC PMC2876398

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Abstract

We evaluated the prevalence of fks1 hot spot (HS) 1 mutations among 133 Candida strains from six species displaying various caspofungin MIC values (from < or =0.008 to >8 microg/ml). Only 4 (2.9%) strains displayed FKS1 HS1 amino acid substitutions: 1 C. albicans (F641Y) among 32 isolates tested (3.1%), 1 C. glabrata (S645P) among 34 isolates tested (2.9%), and 2 C. tropicalis (F641S) among 12 isolates tested (16.7%). The 4 isolates displaying FKS1 HS1 alterations showed elevated caspofungin MIC results (1 to >8 microg/ml) but lower anidulafungin and micafungin MIC values (0.12 to 4 microg/ml and 0.25 to 4 microg/ml, respectively) in some instances within the wild-type MIC population, as determined using the epidemiologic cutoff values (ECV). Candida krusei, C. parapsilosis, and C. guilliermondii isolates tested showed no FKS1 HS1 alterations regardless of echinocandin MIC result. We additionally analyzed 8 C. albicans and 7 C. glabrata strains for mutations on other HS regions of fks1 and fks2. Three C. glabrata strains showed alterations on FKS2 HS1 (two S645P and one L644W). In general, strains displaying S645P alteration showed higher echinocandin MIC values than strains harboring other mutations. Overall, Candida spp. strains showing caspofungin MIC values within the ECV did not display fks HS mutations. In contrast, strains showing alterations in this region displayed anidulafungin and/or micafungin MIC values within the wild-type population, suggesting that caspofungin could be the most sensitive agent for detection of these resistance mutations. Furthermore, results from this large, geographically diverse Candida spp. collection demonstrated that fks1 HS1 mutations remain uncommon among isolates with various echinocandin MIC levels.

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Additional resistance mechanisms may remain to be described given that Fks mutations have not been identified in some echinocandin-resistant isolates and that isolates with identical Fks mutations exhibit different resistance phenotypes.
“Additional resistance mechanisms may remain to be described given that Fks mutations have not been identified in some echinocandin-resistant isolates [20], [37], [40], and that isolates with identical Fks mutations exhibit different resistance phenotypes with distinct responses to cellular perturbations [41].”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [40]
The Abstract and Results and Discussion report isolates with elevated echinocandin MICs but no fks1 hot spot 1 alteration. That supports the cited point in a narrower form: the paper tested other FKS hot spots only in a subset, so it does not establish that those isolates lacked all Fks mutations. The distinct-phenotypes clause is attached to a different citation and is not judged here. (LLM, conf=0.82)
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FKS polymorphisms have been suggested to reduce the affinity of glucan synthase to echinocandins by two to three orders of magnitude compared to the wild-type enzyme.
“It has been suggested that these FKS polymorphisms reduce the affinity to echinocandins of the glucan synthase by two to three orders of magnitude compared to the wild-type enzyme [106,107].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [106]

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Low prevalence of fks1 hot spot 1 mutations in a worldwide collection of Candida strains. Antimicrob. Agents Chemother
Castanheira, M., Woosley, L. N., Diekema, D. J., Messer, S. A., Jones, R. N., & Pfaller, M. A. (2010)
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Mutations in the fks1 Gene in Candida albicans , C. tropicalis , and C. krusei Correlate with Elevated Caspofungin MICs Uncovered in AM3 Medium Using the Method of the European Committee on Antibiotic Susceptibility Testing
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Authors: Castanheira, M., Woosley, L. N., Diekema, D. J., Messer, S. A., Jones, R. N., & Pfaller, M. A.
Affiliations: JMI Laboratories (US)
University of Iowa (US)
ORCID: Castanheira, Mariana
Woosley, Leah N.
Diekema, Daniel J.
Messer, Shawn A.
Jones, Ronald N.
Pfaller, Michael A.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2010-06
Volume: 54
Issue: 6
Pages: 2655-2659
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.01711-09
PMC: PMC2876398
OpenAlex: W2027821217
Cited by: 125
References: 16
Citations by year: 2026: 4 · 2025: 6 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 8 · 2018: 6 · 2017: 9 · 2016: 6 · 2015: 9 · 2014: 15 · 2013: 4 · 2012: 13
FWCI: 7.88
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Pfizer
Astellas Pharma
Astellas Pharma Global Development
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: Candida, echinocandin resistance, caspofungin, anidulafungin, micafungin, FKS1, FKS2, Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida parapsilosis, Candida guilliermondii, antifungal susceptibility
MeSH terms: Amino Acid Sequence, Antifungal Agents, Base Sequence, Candida, Candida albicans, Candidiasis, DNA, Fungal, Fungal Proteins, Genes, Fungal, Humans, Microbial Sensitivity Tests, Molecular Sequence Data, Mutation, Species Specificity, Sequence Homology, Amino Acid, Amino Acid Substitution, Drug Resistance, Fungal, Candida glabrata, Echinocandins, In Vitro Techniques

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Low Prevalence of fks1 Hot Spot 1 Mutations in a Worldwide Collection of Candida Strains

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