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

Desnos-Ollivier, Marie; Bretagne, Stéphane; Raoux, Dorothée; Hoinard, Damien; Dromer, Françoise; Dannaoui, Eric

doi:10.1128/aac.00088-08

Cited by 132Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

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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Desnos-Ollivier, Marie, Bretagne, Stéphane, Raoux, Dorothée, Hoinard, Damien, Dromer, Françoise, Dannaoui, Eric·2008·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.00088-08PMC PMC2533459

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Abstract

Mutations in two specific regions of the Fks1 subunit of 1,3-beta-D-glucan synthase are known to confer decreased caspofungin susceptibility on Candida spp. Clinical isolates of Candida spp. (404 Candida albicans, 62 C. tropicalis, and 21 C. krusei isolates) sent to the French National Reference Center were prospectively screened for susceptibility to caspofungin in vitro by the broth microdilution reference method of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing (AFST-EUCAST). Twenty-eight isolates (25 C. albicans, 2 C. tropicalis, and 1 C. krusei isolate) for which the caspofungin MIC was above the MIC that inhibited 90% of the isolates of the corresponding species (MIC(90)) were subjected to molecular analysis in order to identify mutations in the fks1 gene. Substitutions in the deduced protein sequence of Fks1 were found for 8 isolates, and 20 isolates had the wild-type sequence. Among the six C. albicans isolates harboring mutations, six patterns were observed involving amino acid changes at positions 641, 645, 649, and 1358. For C. tropicalis, one isolate showed an L644W mutation, and for one C. krusei isolate, two mutations, L658W and L701M, were found. Two media, RPMI medium and AM3, were tested for their abilities to distinguish between isolates with wild-type Fks1 and those with mutant Fks1. In RPMI medium, caspofungin MICs ranged from 0.25 to 2 microg/ml for wild-type isolates and from 1 to 8 micro for mutant isolates. A sharper difference was observed in AM3: all wild-type isolates were inhibited by 0.25 micro of caspofungin, while caspofungin MICs for all mutant isolates were >or=0.5 microg/ml. These data demonstrate that clinical isolates of C. albicans, C. tropicalis, and C. krusei with decreased susceptibility to caspofungin in vitro have diverse mutations in the fks1 gene and that AM3 is potentially a better medium than RPMI for distinguishing between mutant and wild-type isolates using the AFST-EUCAST method.

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Echinocandin resistance has been found in most clinically relevant Candida species.
“It has been found in most clinically relevant Candida species, but is most common in C. glabrata with rates exceeding 10% at selected institutions.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [11]
Echinocandin resistance has emerged in Candida over recent years.
“Echinocandin resistance has emerged over the recent years.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [11]
Most reports of acquired echinocandin resistance are case reports or case series, which collectively document the potential of resistance development in almost all species that are not intrinsically susceptible.
“Most are case reports or case series, which collectively document the potential of resistance development in almost all species that are not intrinsically susceptible (9–15).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [11]
Acquired echinocandin resistance has been reported in single isolates belonging to most Candida species including C. albicans, C. dubliniensis, C. kefyr, C. glabrata, C. krusei, C. lusitaniae and C. tropicalis.
“Moreover, reports on acquired echinocandin resistance, defined as resistance among species that are normally susceptible, have emerged and today acquired resistance has been reported in single isolates belonging to most Candida species including C. albicans, C. dubliniensis, C. kefyr, C. glabrata, C. krusei, C. lusitaniae and C. tropicalis (9–15).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [11]
Clinically relevant acquired echinocandin resistance in Candida has never been detected in the absence of FKS hot spot mutations.
“So far, clinically relevant acquired echinocandin resistance in Candida has never been detected in absence of FKS hot spot mutations.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [11]

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Authors: Desnos-Ollivier, M., Bretagne, S., Raoux, D., Hoinard, D., Dromer, F., & Dannaoui, E.
Affiliations: Institut Pasteur, Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, CNRS URA3012, 75724 Paris Cedex 15
Centre National de la Recherche Scientifique (FR)
ORCID: Hoinard, Damien
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2008-09
Volume: 52
Issue: 9
Pages: 3092-3098
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.00088-08
PMC: PMC2533459
OpenAlex: W2014642379
Cited by: 132
References: 29
Citations by year: 2026: 4 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 6 · 2020: 9 · 2019: 4 · 2018: 4 · 2017: 10 · 2016: 8 · 2015: 2 · 2014: 8 · 2013: 7 · 2012: 10
FWCI: 8.72
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)
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: FKS1, 1,3-β-D-glucan synthase, Candida albicans, Candida tropicalis, Candida krusei, antifungal resistance, RPMI medium, antifungal susceptibility testing, clinical isolates, amino acid substitutions
MeSH terms: Caspofungin, Antifungal Agents, Base Sequence, Candida, Candida albicans, Culture Media, Europe, Fungal Proteins, Glucosyltransferases, Humans, Microbial Sensitivity Tests, Molecular Sequence Data, Mutation, Drug Resistance, Fungal, Candida tropicalis, Echinocandins, Lipopeptides

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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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