Multiple Molecular Mechanisms Contribute to a Stepwise Development of Fluconazole Resistance in Clinical Candida albicans Strains

Franz, Renate; Kelly, Steven L.; Lamb, David C.; Kelly, Diane E.; Ruhnke, Markus; Morschhäuser, Joachim

doi:10.1128/aac.42.12.3065

Cited by 339Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Multiple Molecular Mechanisms Contribute to a Stepwise Development of Fluconazole Resistance in Clinical Candida albicans Strains

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Franz, Renate, Kelly, Steven L., Lamb, David C., Kelly, Diane E., Ruhnke, Markus, Morschhäuser, Joachim·1998·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.42.12.3065PMC PMC106000

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Abstract

From each of two AIDS patients with oropharyngeal candidiasis, five Candida albicans isolates from recurrent episodes of infection which became gradually resistant against fluconazole during antimycotic treatment were analyzed for molecular changes responsible for drug resistance. In both patients, a single C. albicans strain was responsible for the recurrent infections, but the CARE-2 fingerprint pattern of the isolates exhibited minor genetic alterations, indicating that microevolution of the strains took place during fluconazole therapy. In the isolates from patient 1, enhanced mRNA levels of the MDR1 gene, encoding a multiple drug resistance protein from the superfamily of major facilitators, and constitutive high expression of the ERG11 gene, coding for the drug target enzyme sterol 14alpha-demethylase, correlated with a stepwise development of fluconazole resistance. The resistant strains exhibited reduced accumulation of fluconazole and, for the last in the series, a slight increase in drug needed to inhibit sterol 14alpha-demethylation in vitro. In the isolates from patient 2, increased MDR1 mRNA levels and the change from heterozygosity to homozygosity for a mutant form of the ERG11 gene correlated with continuously decreased drug susceptibility. In this series, reduced drug accumulation and increased resistance in the target enzyme activity, sterol 14alpha-demethylase, were observed. These results demonstrate that different molecular mechanisms contribute to a gradual development of fluconazole resistance in C. albicans.

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A link was established between the MDR1 gene and fluconazole resistance when serial isolates from HIV-infected patients with oropharyngeal candidiasis were analysed for ERG11 and MDR1 mRNA expression levels.
“It was not until serial isolates taken from HIV-infected patients with oropharyngeal candidiasis were analysed for ERG11 and MDR1 mRNA expression levels that a link was established between the MDR1 gene and fluconazole resistance.98”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [98]
Overexpression of ERG11 contributes to decreased azole susceptibility through increased production of the azole target 14α-lanosterol demethylase.
“The overexpression of ERG11 had been shown to contribute to decreased azole susceptibility through increased production of the azole target 14α-lanosterol demethylase (Figure 1a).78 , 98 , 106 , 107”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [98]

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Authors: Franz, R., Kelly, S. L., Lamb, D. C., Kelly, D. E., Ruhnke, M., & Morschhäuser, J.
Affiliations: University of Würzburg (DE)
Aberystwyth University (GB)
Humboldt-Universität zu Berlin (DE)
Zentrum für Infektionsforschung, Universität Würzburg, D-97070 Würzburg,1 and
ORCID: Kelly, Steven L.
Lamb, David C.
Kelly, Diane E.
Ruhnke, Markus
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 1998-12
Volume: 42
Issue: 12
Pages: 3065-3072
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.42.12.3065
PMC: PMC106000
OpenAlex: W2160765565
Cited by: 339
References: 38
Citations by year: 2026: 6 · 2025: 4 · 2024: 7 · 2023: 9 · 2022: 4 · 2021: 11 · 2020: 14 · 2019: 15 · 2018: 8 · 2017: 14 · 2016: 11 · 2015: 10 · 2014: 16 · 2013: 12 · 2012: 7
FWCI: 9.08
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)
Europe PMC (PubMed Central) (publishedVersion)
PubMed (publishedVersion)
Funders: Bundesministerium für Bildung und Forschung
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, fluconazole resistance, oropharyngeal candidiasis, AIDS, MDR1 gene, ERG11, sterol 14α-demethylase, major facilitator superfamily, drug accumulation, microevolution, recurrent infections, antifungal resistance mechanisms
MeSH terms: Alleles, Antifungal Agents, Candida albicans, Candidiasis, Cytochrome P-450 Enzyme System, Drug Resistance, Microbial, Gene Expression Regulation, Humans, Gas Chromatography-Mass Spectrometry, Microbial Sensitivity Tests, Nucleic Acid Hybridization, Oxidoreductases, RNA, Bacterial, Blotting, Southern, Blotting, Northern, Fluconazole, AIDS-Related Opportunistic Infections, Genes, MDR, Sterol 14-Demethylase

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Multiple Molecular Mechanisms Contribute to a Stepwise Development of Fluconazole Resistance in Clinical Candida albicans Strains

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