Activation of the Multiple Drug Resistance Gene MDR1 in Fluconazole-Resistant, Clinical Candida albicans Strains Is Caused by Mutations in a trans -Regulatory Factor

Wirsching, Stephanie; Michel, Sonja; Köhler, Gerwald; Morschhäuser, Joachim

doi:10.1128/jb.182.2.400-404.2000

Cited by 88Antifungal resistance and susceptibilityDrug Transport and Resistance MechanismsFungal and yeast genetics research

Activation of the Multiple Drug Resistance Gene MDR1 in Fluconazole-Resistant, Clinical Candida albicans Strains Is Caused by Mutations in a trans -Regulatory Factor

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Wirsching, Stephanie, Michel, Sonja, Köhler, Gerwald, Morschhäuser, Joachim·2000·Journal of Bacteriology

DOI 10.1128/jb.182.2.400-404.2000PMC PMC94289

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Abstract

Resistance of Candida albicans against the widely used antifungal agent fluconazole is often due to active drug efflux from the cells. In many fluconazole-resistant C. albicans isolates the reduced intracellular drug accumulation correlates with constitutive strong expression of the MDR1 gene, encoding a membrane transport protein of the major facilitator superfamily that is not detectably expressed in vitro in fluconazole-susceptible isolates. To elucidate the molecular changes responsible for MDR1 activation, two pairs of matched fluconazole-susceptible and resistant isolates in which drug resistance coincided with stable MDR1 activation were analyzed. Sequence analysis of the MDR1 regulatory region did not reveal any promoter mutations in the resistant isolates that might account for the altered expression of the gene. To test for a possible involvement of trans-regulatory factors, a GFP reporter gene was placed under the control of the MDR1 promoter from the fluconazole-susceptible C. albicans strain CAI4, which does not express the MDR1 gene in vitro. This MDR1P-GFP fusion was integrated into the genome of the clinical C. albicans isolates with the help of the dominant selection marker MPA(R) developed for the transformation of C. albicans wild-type strains. Integration was targeted to an ectopic locus such that no recombination between the heterologous and resident MDR1 promoters occurred. The transformants of the two resistant isolates exhibited a fluorescent phenotype, whereas transformants of the corresponding susceptible isolates did not express the GFP gene. These results demonstrate that the MDR1 promoter was activated by a trans-regulatory factor that was mutated in fluconazole-resistant isolates, resulting in deregulated, constitutive MDR1 expression.

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Fluconazole-susceptible and fluconazole-resistant matched pairs were shown to lack major polymorphic differences in the nucleotide sequence of their respective MDR1 promoter regions, despite high expression of MDR1 mRNA in the fluconazole-resistant isolate.
“Importantly, fluconazole-susceptible and fluconazole-resistant matched pairs (serial isolates taken from the same patient in which fluconazole resistance developed over time) were shown to lack major polymorphic differences in the nucleotide sequence of their respective MDR1 promoter regions, despite high expression of MDR1 mRNA in the fluconazole-resistant isolate.101”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [101]
Subsequent expression of GFP from the MDR1 promoter in the fluconazole-resistant isolate but not the fluconazole-susceptible isolate indicated that MDR1 expression was likely guided by a trans-regulatory factor.
“Subsequent expression of GFP from the MDR1 promoter in the fluconazole-resistant isolate but not the fluconazole-susceptible isolate indicated that MDR1 expression was likely guided by a trans-regulatory factor.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [101]

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Authors: Wirsching, S., Michel, S., Köhler, G., & Morschhäuser, J.
Affiliations: University of Würzburg (DE)
Zentrum für Infektionsforschung, Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Germany
Venue: Journal of Bacteriology
Publisher: American Society for Microbiology
Published: 2000-01-15
Volume: 182
Issue: 2
Pages: 400-404
ISSN: 0021-9193 (ISSN-L)
1098-5530
DOI: 10.1128/jb.182.2.400-404.2000
PMC: PMC94289
OpenAlex: W2131106578
Cited by: 88
References: 31
Citations by year: 2026: 1 · 2025: 1 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 5 · 2012: 2
FWCI: 4.94
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Bacteriology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Bundesministerium für Bildung und Forschung
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: Candida albicans, fluconazole resistance, MDR1 gene, multidrug resistance, transcriptional activation, MDR1 promoter, drug efflux, antifungal resistance, GFP reporter, clinical isolates
MeSH terms: Candida albicans, Genes, Regulator, Luminescent Proteins, Mutation, Promoter Regions, Genetic, Recombinant Fusion Proteins, RNA, Messenger, Fluconazole, Gene Expression Regulation, Fungal, Sequence Analysis, DNA, Drug Resistance, Multiple, ATP Binding Cassette Transporter, Subfamily B, Member 1, Green Fluorescent Proteins

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Activation of the Multiple Drug Resistance Gene MDR1 in Fluconazole-Resistant, Clinical Candida albicans Strains Is Caused by Mutations in a trans -Regulatory Factor

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