A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis , Candida orthopsilosis , and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility
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Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis . All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans . Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V max values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae . The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
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Species more tolerant to echinocandins include C. parapsilosis, C. orthopsilosis, C. metapsilosis, C. guillerimondii, C. lipolytica, and C. fermentati.
“Among the species more tolerant to echinocandins, besides C. parapsilosis, we can find C. orthopsilosis, C. metapsilosis, C. guillerimondii, C. lipolytica, and C. fermentati [33,34,35].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [35]
Many resistance-causing sequence variations are constitutive in species showing a higher intrinsic tolerance towards echinocandins.
“Notably, many of these resistance-causing sequence variations are constitutive in species showing a higher intrinsic tolerance towards echinocandins (e.g., C. parapsilosis, C. orthopsilosis, C. metapsilosis, C. guillerimondii, and C. lipolytica) [34,35].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [35]
C. parapsilosis and C. guilliermondii are intrinsically less susceptible to echinocandins, reflecting naturally occurring polymorphisms in the FKS1 hotspot regions of these species.
“C. parapsilosis and C. guilliermondii are intrinsically less susceptible to echinocandins, reflecting naturally occurring polymorphisms in the FKS1 hotspot regions of these species [19].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [19]
Some Candida spp. are inherently less susceptible in vitro due to naturally occurring polymorphisms in the target protein.
“However, some Candida spp. are inherently less susceptible in vitro due to naturally occurring polymorphisms in the target protein (Table 1) (7).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [7]
The echinocandin MIC is approximately 7-fold higher against C. parapsilosis, which has a naturally occurring alteration in the target gene.
“For example, the echinocandin MIC is approx. 7-fold higher against C. parapsilosis, which has a naturally occurring alteration in the target gene (Table 1).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [7]
Intrinsic target gene alterations are found in C. parapsilosis, C. metapsilosis, C. orthopsilosis, C. guilliermondii and C. lipolytica.
“Intrinsic target gene alterations are found in C. parapsilosis, C. metapsilosis, C. orthopsilosis, C. guilliermondii and C. lipolytica (Table 1) (7;26).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [7]
Polymorphisms occur at codon V641 in FKS1 and V1374 in FKS2 in Saccharomyces cerevisiae, which is in general slightly less echinocandin susceptible than C. albicans and C. glabrata.
“Additionally, polymorphisms occur at codon I660 in hot spot 1 of FKS1 in C. krusei, for which the in vitro micafungin MIC is elevated approx. 2-fold and at codon V641 in FKS1 and V1374 in FKS2 in Saccharomyces cerevisiae, which is in general slightly less echinocandin susceptible than C. albicans and C. glabrata.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [7]
Polymorphisms occur at codon I660 in hot spot 1 of FKS1 in C. krusei, for which the in vitro micafungin MIC is elevated approximately 2-fold.
“Additionally, polymorphisms occur at codon I660 in hot spot 1 of FKS1 in C. krusei, for which the in vitro micafungin MIC is elevated approx. 2-fold and at codon V641 in FKS1 and V1374 in FKS2 in Saccharomyces cerevisiae, which is in general slightly less echinocandin susceptible than C. albicans and C. glabrata.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [7]
Intrinsic echinocandin resistance of C. parapsilosis, C. orthopsilosis, C. metapsilosis, and C. guilliermondii has been described.
“In addition, intrinsic echinocandin resistance of C. parapsilosis, C. orthopsilosis, C. metapsilosis, and C. guilliermondii has been described [117, 118].”
From <i>Candida</i>Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [117]
Intrinsic FKS mutations result in elevated MIC levels but lower level of reduced β-1,3-d-glucan synthase sensitivity compared with acquired FKS mutations.
“intrinsic FKS mutations, also resulting in elevated MIC levels (but in a lower level of reduced β-1,3-d-glucan synthase sensitivity when compared with the acquired FKS mutations) [118,120,121].”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [121]
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Self-citationDiagnostics and Susceptibility Testing in <i>Aspergillus</i>
Bernal-Martínez, L., Alastruey-Izquierdo, A., & Cuenca-Estrella, M. (2016) · Future Microbiology · doi:10.2217/fmb.15.140 · Cited by 25 · see citing works
Ceballos-Garzon, A., Monteoliva, L., Gil, C., Alvarez-Moreno, C., Vega-Vela, N. E., Engelthaler, D. M., Bowers, J., Le Pape, P., & Parra-Giraldo, C. M. (2022) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkab454 · Cited by 18 · see citing works
Arastehfar, A., Daneshnia, F., Floyd, D. J., Jeffries, N. E., Salehi, M., Perlin, D. S., Ilkit, M., Lass-Flöerl, C., & Mansour, M. K. (2024) · mBio · doi:10.1128/mbio.00072-24 · Cited by 19 · see citing works
Self-citationInsight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance
Su, Y., Li, Y., Yi, Q., Xu, Y., Sun, T., & Li, Y. (2025) · Journal of Fungi · doi:10.3390/jof11020143 · Cited by 18 · see citing works
“Currently, resistance to echinocandins is mainly associated with mutations in the FKS1/FKS2 genes [82,90,91].”
Gonzalez-Jimenez, I., Keniya, M. V., Aptekmann, A. A., Quinteros, C., Wilkerson, A., Arastehfar, A., Daneshnia, F., Perlin, D. S., & Shor, E. (2025) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00500-25 · Cited by 4 · see citing works
Self-citation
- Authors
- Garcia-Effron, G., Katiyar, S. K., Park, S., Edlind, T. D., & Perlin, D. S.
- Affiliations
- Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
- Rutgers New Jersey Medical School (US)
- Drexel University (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2008-07
- Volume
- 52
- Issue
- 7
- Pages
- 2305-2312
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC2443908
- OpenAlex
- W2005936443
- Cited by
- 323
- References
- 36
- Citations by year
- 2026: 20 · 2025: 16 · 2024: 12 · 2023: 20 · 2022: 12 · 2021: 12 · 2020: 22 · 2019: 8 · 2018: 16 · 2017: 25 · 2016: 13 · 2015: 11 · 2014: 20 · 2013: 11 · 2012: 22
- FWCI
- 17.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R03AI054289, 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 › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida parapsilosis, Candida orthopsilosis, Candida metapsilosis, echinocandin resistance, glucan synthase, caspofungin, micafungin, anidulafungin, enzyme kinetics, Vmax, Candida albicans, Candida glabrata, antifungal susceptibility
- MeSH terms
- Amino Acid Sequence, Antifungal Agents, Base Sequence, Candida, Candidiasis, DNA, Fungal, Enzyme Inhibitors, Fungal Proteins, Genes, Fungal, Glucosyltransferases, Humans, Membrane Proteins, Molecular Sequence Data, Species Specificity, Gene Expression, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, DNA Primers, Amino Acid Substitution, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins, Echinocandins
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