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Correlating Echinocandin MIC and Kinetic Inhibition of fks1 Mutant Glucan Synthases for Candida albicans : Implications for Interpretive Breakpoints
Open accessAbstract
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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“Given that specific Fks amino acid substitutions that decrease sensitivity of the 1,3-β-D-glucan synthase enzyme to echinocandins also reduce the enzyme catalytic capacity, the Fks2 S663P mutation may confer a fitness cost in terms of reduced growth or viability in the absence of the drug [36], [39].”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [39]
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“Mutations in FKS1 did not alter substrate binding but lowered V max values [122].”
From Candida Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [122]
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Cites
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Resistance to echinocandin-class antifungal drugs.
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Self-citationPerea, S., López-Ribot, J. L., Kirkpatrick, W. R., McAtee, R. K., Santillán, R. A., Martı́nez, M., Calabrese, D., Sanglard, D., & Patterson, T. F. (2001) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.45.10.2676-2684.2001 · Cited by 470
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Discovery of Novel Antifungal (1,3)-β- d -Glucan Synthase Inhibitors
Onishi, J. C., Meinz, M., Thompson, J. R., Curotto, J. E., Dreikorn, S., Rosenbach, M. J., Douglas, C. M., Abruzzo, G. K., Flattery, A. M., Kong, L., et al. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.2.368-377.2000 · Cited by 329
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Metadata
- 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.
- 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
- 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
- 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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