Regulated overexpression of CDR1 in Candida albicans confers multidrug resistance
Abstract
OBJECTIVES: Information on the function of Candida albicans ATP-binding cassette (ABC) membrane transporter Cdr1p has come from studying the effect of gene inactivation in C. albicans and from heterologous Cdr1p expression in the yeast Saccharomyces cerevisiae. These approaches, however, give only an indirect indication of Cdr1p function in C. albicans itself. The objective of this study was to determine Cdr1p function in C. albicans by induced overexpression of Cdr1p in a C. albicans CDR1-deleted strain. METHODS: The C. albicans CDR1 open reading frame was fused to the C. albicans HEX1 promoter and used to complement a CDR1-null mutant to create strain FL3. The effect of inducing the FL3 HEX1 promoter, by growth on medium containing N-acetylglucosamine (GlcNAc) as the carbon source, on CDR1 expression and drug susceptibility was determined. RESULTS: C. albicans FL3 cells grown on medium containing GlcNAc overexpressed CDR1 mRNA and a 170 kDa plasma membrane protein that reacted with anti-Cdr1p antibodies. Overexpression of Cdr1p in C. albicans FL3 conferred resistance to structurally unrelated chemicals such as terbinafine, brefeldin A, cerulenin and nigericin as well as to azole antifungal agents, but not resistance to polyene antibiotics. FK506, ascomycin and ciclosporin A chemosensitized FL3 to fluconazole. FL3 cells grown on GlcNAc effluxed 5.3 times as much Cdr1p substrate rhodamine 6G, over a 10 min period, as FL3 cells grown on glucose, and this rhodamine 6G efflux was inhibited by including fluconazole in the assay. CONCLUSION: This study provides the first direct demonstration of Cdr1p pump activity in C. albicans.
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In two separate studies, isolates of C. albicans taken from HIV-infected individuals had increased mRNA levels of CDR1, which has been shown to confer resistance to the azole antifungals.
“In two separate studies, it was found that isolates of C. albicans taken from HIV-infected individuals had increased mRNA levels of CDR1, which has been shown to confer resistance to the azole antifungals.77–79”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [79]
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- Authors
- Niimi, M., Niimi, K., Takano, Y., Holmes, A. R., Fischer, F. J., Uehara, Y., & Cannon, R. D.
- Affiliations
- University of Otago (NZ)
- Corresponding author
- Niimi, Masakazu
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-12-01
- Volume
- 54
- Issue
- 6
- Pages
- 999-1006
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- OpenAlex
- W2126671024
- Cited by
- 69
- References
- 46
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 2 · 2012: 4
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Health Research Council of New Zealand
- 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, Cdr1p, ABC transporters, multidrug resistance, drug efflux, azole resistance, terbinafine, brefeldin A, cerulenin, nigericin, FK506, cyclosporine, ascomycin, plasma membrane proteins
- MeSH terms
- Acetylglucosaminidase, Antifungal Agents, Candida albicans, Culture Media, Fungal Proteins, Humans, Microbial Sensitivity Tests, Fluconazole, Up-Regulation, Gene Expression Regulation, Fungal, Drug Resistance, Multiple, Fungal, Membrane Transport Proteins
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