Relative Contributions of the Candida albicans ABC Transporters Cdr1p and Cdr2p to Clinical Azole Resistance
Open accessAbstract
Candida albicans frequently develops resistance to treatment with azole drugs due to the acquisition of gain-of-function mutations in the transcription factor Tac1p. Tac1p hyperactivation in azole-resistant isolates results in the constitutive overexpression of several genes, including CDR1 and CDR2, which encode two homologous transporters of the ATP-binding cassette family. Functional studies of Cdr1p and Cdr2p have been carried out so far by heterologous expression in the budding yeast Saccharomyces cerevisiae and by gene deletion or overexpression in azole-sensitive C. albicans strains in which CDR1 expression is low and CDR2 expression is undetectable. Thus, the direct demonstration that CDR1 and CDR2 overexpression causes azole resistance in clinical strains is still lacking, as is our knowledge of the relative contribution of each transporter to clinical azole resistance. In the present study, we used the SAT1 flipper system to delete the CDR1 and CDR2 genes from clinical isolate 5674. This strain is resistant to several azole derivatives due to a strong hyperactive mutation in Tac1p and expresses high levels of Cdr1p and Cdr2p. We found that deleting CDR1 had a major effect, reducing resistance to fluconazole (FLC), ketoconazole (KTC), and itraconazole (ITC) by 6-, 4-, and 8-fold, respectively. Deleting CDR2 had a much weaker effect, reducing FLC or KTC resistance by 1.5-fold, and had no effect on ITC resistance. These results demonstrate that Cdr1p is a major determinant of azole resistance in strain 5674 and potentially in other clinical strains overexpressing Cdr1p and Cdr2p, while Cdr2p plays a more minor role.
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Deletion of either of the CDR1/2 genes leads to loss of the resistance phenotype.
“Importantly, the deletion of either of the CDR1/2 genes leads to the loss of the resistance phenotype [78]”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [78]
Deletion of CDR1 in an azole-resistant clinical isolate containing a Tac1 gain-of-function mutation was directly responsible for reducing resistance to fluconazole, ketoconazole and itraconazole.
“It was further demonstrated that deletion of CDR1 in an azole-resistant clinical isolate containing a Tac1 gain-of-function mutation was directly responsible for reducing resistance to fluconazole, ketoconazole and itraconazole.84”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [84]
While CDR2 deletion also reduced resistance to fluconazole and ketoconazole, the effect was much weaker compared with CDR1 deletion, suggesting Cdr1 is the major contributor towards Tac1-mediated azole resistance.
“While CDR2 deletion also reduced resistance to fluconazole and ketoconazole, the effect was much weaker compared with CDR1 deletion, suggesting Cdr1 is the major contributor towards Tac1-mediated azole resistance.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [84]
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- Authors
- Tsao, S., Rahkhoodaee, F., & Raymond, M.
- Affiliations
- Institute for Research in Immunology and Cancer (CA)
- Corresponding author
- Raymond, Martine
- ORCID
- Tsao, Sarah
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2009-04
- Volume
- 53
- Issue
- 4
- Pages
- 1344-1352
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC2663127
- OpenAlex
- W2076308802
- Cited by
- 126
- References
- 45
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 11 · 2019: 15 · 2018: 7 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 2 · 2013: 9 · 2012: 6
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MT-15679)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- Candida albicans, azole resistance, Cdr1p, ABC transporters, gene deletion, fluconazole, ketoconazole, itraconazole, clinical isolates, drug efflux
- MeSH terms
- Antifungal Agents, Azoles, Candida albicans, Fungal Proteins, Ketoconazole, Microbial Sensitivity Tests, Rhodamines, Fluconazole, Itraconazole, ATP-Binding Cassette Transporters, Drug Resistance, Fungal, Membrane Transport Proteins
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