Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents

Sanglard, Dominique; Ischer, Françoise; Parkinson, Tania; Falconer, Derek; Bille, Jacques

doi:10.1128/aac.47.8.2404-2412.2003

Cited by 398Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents

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Sanglard, Dominique, Ischer, Françoise, Parkinson, Tania, Falconer, Derek, Bille, Jacques·2003·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.47.8.2404-2412.2003PMC PMC166068

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Abstract

The role of sterol mutations in the resistance of Candida albicans to antifungal agents has not been thoroughly investigated. Previous work reported that clinical C. albicans strains resistant to both azole antifungals and amphotericin B were defective in ERG3 , a gene encoding sterol Δ 5,6 -desaturase. It is also believed that a deletion of the lanosterol 14α-demethylase gene, ERG11 , is possible only under aerobic conditions when ERG3 is not functional. We tested these hypotheses by creating mutants by targeted deletion of the ERG3 and ERG11 genes and subjecting those mutants to antifungal susceptibility testing and sterol analysis. The homozygous erg3 / erg3 mutant created, DSY1751, was resistant to azole derivatives, as expected. This mutant was, however, slightly more susceptible to amphotericin B than the parent wild type. It was possible to generate erg11 / erg11 mutants in the DSY1751 background but also, surprisingly, in the background of a wild-type isolate with functional ERG3 alleles under aerobic conditions. This mutant (DSY1769) was obtained by exposure of an ERG11 / erg11 heterozygous strain in a medium containing 10 μg of amphotericin B per ml. Amphotericin B-resistant strains were obtained only from ERG11 / erg11 heterozygotes at a frequency of approximately 5 × 10 −5 to 7 × 10 −5 , which was consistent with mitotic recombination between the first disrupted erg11 allele and the other remaining functional ERG11 allele. DSY1769 was also resistant to azole derivatives. The main sterol fraction in DSY1769 contained lanosterol and eburicol. These studies showed that erg11 / erg11 mutants of a C. albicans strain harboring a defective erg11 allele can be obtained in vitro in the presence of amphotericin B. Amphotericin B-resistant strains could therefore be selected by similar mechanisms during antifungal therapy.

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ERG11 can only be disrupted in ERG3-deficient strains or when strains are cultured in media with nystatin or amphotericin B, because sterols with a C14-methyl group or diols, especially 14-methylergosta-8,24(28)-dien-3β,6α-diol accumulated by ERG3, are lethal in C. albicans.
“Interestingly, the direct target gene of azoles, ERG11 , can only be disrupted in the ERG3 -de fi cient strains or when strains are cultured in media with nystatin or amphotericin B, as the sterols with a C14-methyl group or diols especially for 14-methylergosta-8,24(28)-dien-3 b ,6 a -diol accumulated by ERG3 is lethal in C. albicans .”
From The synthesis, regulation, and functions of sterols inCandida albicans: Well-known but still lots to learn (2016) · cites this paper as [33]
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Mutations in Candida albicans ERG6 and ERG3 genes lead to the development of azole resistance.
“Thus, mutations in Candida albicans ERG6 and ERG3 genes lead to the development of azole resistance [19,23].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [23]
Acquired resistance to amphotericin B is rare, and involves reduced ergosterol biosynthesis and the production of alternative sterols to which amphotericin B has low affinity.
“Acquired resistance is also rare, and involves reduced ergosterol biosynthesis and the production of alternative sterols to which amphotericin B has low affinity.”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [65]
Candida strains resistant to amphotericin B were found to harbor mutations in ERG2, ERG3, ERG5, and ERG11, and were co-resistant to fluconazole.
“Candida strains resistant to amphotericin B were found to harbor mutations in ERG2, ERG3, ERG5, and ERG11, and were co-resistant to fluconazole [63,64,65,66].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [65]

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Authors: Sanglard, D., Ischer, F., Parkinson, T., Falconer, D., & Bille, J.
Affiliations: Centre Hospitalier Universitaire Vaudois (CH)
University Hospital Lausanne (CHUV), CH-1011 Lausanne, Switzerland
Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom
Corresponding author: Sanglard, Dominique
ORCID: Sanglard, Dominique
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2003-08
Volume: 47
Issue: 8
Pages: 2404-2412
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.47.8.2404-2412.2003
PMC: PMC166068
OpenAlex: W2163989602
Cited by: 398
References: 37
Citations by year: 2026: 14 · 2025: 21 · 2024: 27 · 2023: 31 · 2022: 23 · 2021: 21 · 2020: 24 · 2019: 20 · 2018: 16 · 2017: 26 · 2016: 17 · 2015: 15 · 2014: 22 · 2013: 14 · 2012: 14
FWCI: 6.26
Type: journal article
Language: en
Open access: green
europepmc.org
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)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Funders: National Research Foundation
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 albicans, ergosterol biosynthesis, ERG3, ERG11, lanosterol 14α-demethylase, azole resistance, amphotericin B resistance, antifungal resistance, mitotic recombination, deletion mutants, lanosterol, sterol analysis
MeSH terms: Aerobiosis, Antifungal Agents, Candida albicans, Ergosterol, Microbial Sensitivity Tests, Mutation, Oxidoreductases, Phenotype, Blotting, Southern, Blotting, Northern, DNA Probes, Reverse Transcriptase Polymerase Chain Reaction, Drug Resistance, Fungal

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Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents

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