Cited by 258Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

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Correlating Echinocandin MIC and Kinetic Inhibition of fks1 Mutant Glucan Synthases for Candida albicans : Implications for Interpretive Breakpoints

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Garcia-Effron, Guillermo, Park, Steven, Perlin, David S.·2009·Antimicrobial Agents and Chemotherapy

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Abstract

ABSTRACT A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-β- d -glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K i increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K m values, although some mutations decreased the V max . Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-β- d -glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of ≥2 μg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of ≤50-fold for the K i was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of ≥0.5 μg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of ≥2 μg/ml for the three echinocandin drugs. The 1,3-β- d -glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans , but a lower susceptibility breakpoint (≤0.5 μg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.

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Authors: Garcia-Effron, G., Park, S., & Perlin, D. S.
Affiliations: Public Health Research Institute, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103
Rutgers New Jersey Medical School (US)
Corresponding author: Perlin, David S.
ORCID: Park, Steven
Perlin, David S.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2009-01
Volume: 53
Issue: 1
Pages: 112-122
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.01162-08
PMC: PMC2612148
OpenAlex: W2116629209
Cited by: 256
References: 55
Citations by year: 2026: 8 · 2025: 10 · 2024: 4 · 2023: 17 · 2022: 4 · 2021: 10 · 2020: 8 · 2019: 13 · 2018: 12 · 2017: 19 · 2016: 8 · 2015: 10 · 2014: 16 · 2013: 17 · 2012: 18
FWCI: 17.66
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)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Astellas Pharma
National Institutes of Health
National Institute of Allergy and Infectious Diseases (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
Life Sciences › Agricultural and Biological Sciences › Plant Science › Fungal Plant Pathogen Control
Keywords: echinocandins, Candida albicans, FKS1 mutations, 1,3-β-D-glucan synthase, enzyme kinetics, caspofungin, micafungin, anidulafungin, susceptibility breakpoints, antifungal resistance, serum interference, clinical isolates
MeSH terms: Caspofungin, Micafungin, Anidulafungin, Candida albicans, Fungal Proteins, Glucosyltransferases, Microbial Sensitivity Tests, Echinocandins, Lipopeptides

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Correlating Echinocandin MIC and Kinetic Inhibition of fks1 Mutant Glucan Synthases for Candida albicans : Implications for Interpretive Breakpoints

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