Rapid, Transient Fluconazole Resistance in Candida albicans Is Associated with Increased mRNA Levels of CDR
Open accessAbstract
Fluconazole-resistant Candida albicans , a cause of recurrent oropharyngeal candidiasis in patients with human immunodeficiency virus infection, has recently emerged as a cause of candidiasis in patients receiving cancer chemotherapy and marrow transplantation (MT). In this study, we performed detailed molecular analyses of a series of C. albicans isolates from an MT patient who developed disseminated candidiasis caused by an azole-resistant strain 2 weeks after initiation of fluconazole prophylaxis (K. A. Marr, T. C. White, J. A. H. vanBurik, and R. A. Bowden, Clin. Infect. Dis. 25:908–910, 1997). DNA sequence analysis of the gene ( ERG11 ) for the azole target enzyme, lanosterol demethylase, revealed no difference between sensitive and resistant isolates. A sterol biosynthesis assay revealed no difference in sterol intermediates between the sensitive and resistant isolates. Northern blotting, performed to quantify mRNA levels of genes encoding enzymes in the ergosterol biosynthesis pathway ( ERG7 , ERG9 , and ERG11 ) and genes encoding efflux pumps ( MDR1 , ABC1 , YCF , and CDR ), revealed that azole resistance in this series is associated with increased mRNA levels for members of the ATP binding cassette (ABC) transporter superfamily, CDR genes. Serial growth of resistant isolates in azole-free media resulted in an increased susceptibility to azole drugs and corresponding decreased mRNA levels for the CDR genes. These results suggest that C. albicans can become transiently resistant to azole drugs rapidly after exposure to fluconazole, in association with increased expression of ABC transporter efflux pumps.
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By altering gene dosage or expression levels, aneuploidy allows fungi to quickly adjust to adverse conditions without permanent genetic mutations, promoting survival in fluctuating environments.
“By altering gene dosage or expression levels, aneuploidy allows fungi to quickly adjust to adverse conditions without permanent genetic mutations, promoting survival in fluctuating environments [99,129,145,152,154].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [145]
The induction effect of fluconazole on heteroresistance involved elevation of mRNA levels for ABC superfamily CDR genes.
“Marr et al. demonstrated that the induction effect of fluconazole on heteroresistance involved elevation of mRNA levels for ABC superfamily CDR genes [145].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [145]
Failure to accumulate the drug intracellularly may be caused by lack of drug penetration due to changes in membrane lipids and sterols or by active efflux of drugs, particularly from overexpression of CDR1, CDR2, and MDR1.
“failure to accumulate the drug intracellularly, which may be caused by the lack of drug penetration, due to changes in membrane lipids and sterols (28), or by active efflux of drugs, resulting particularly from overexpression of the CDR1, CDR2, and MDR1 genes (3, 38, 62, 73)”
From Transcriptional profiling of azole-resistant Candida parapsilosis strains (2011) · cites this paper as [38]
Previous studies with C. albicans, C. dubliniensis, and C. tropicalis demonstrated that resistance to fluconazole can be promoted following repeated in vitro exposure to the drug.
“Previous studies with C. albicans (38), C. dubliniensis (59), and C. tropicalis (9) demonstrated that resistance to fluconazole can be promoted following repeated in vitro exposure to the drug.”
From Transcriptional profiling of azole-resistant Candida parapsilosis strains (2011) · cites this paper as [38]
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“Marr et al. demonstrated that the induction effect of fluconazole on heteroresistance involved elevation of mRNA levels for ABC superfamily CDR genes [145].”
- Authors
- Marr, K. A., Lyons, C. N., Rustad, T., Bowden, R. A., & White, T. C.
- Affiliations
- University of Washington (US)
- Center for Infectious Disease Research (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1998-10
- Volume
- 42
- Issue
- 10
- Pages
- 2584-2589
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC105901
- OpenAlex
- W2120849142
- Cited by
- 166
- References
- 36
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 4 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 2 · 2015: 4 · 2014: 9 · 2013: 4 · 2012: 10
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Update notices
- correction (1999-02-01)
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- M.J. Murdock Charitable Trust
- National Institutes of Health
- National Cancer Institute (CA18029 22, P01CA018029)
- National Institute of Allergy and Infectious Diseases (2T32 AI108044-21)
- National Institute of Dental and Craniofacial Research (R01DE011367, R01 DE-11367)
- 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, ABC transporters, efflux pumps, azole resistance, ERG11, sterol biosynthesis, mRNA expression, systemic candidiasis, bone marrow transplantation, antifungal prophylaxis
- MeSH terms
- Antifungal Agents, Candida albicans, Drug Resistance, Microbial, Ergosterol, RNA, Messenger, Fluconazole, ATP-Binding Cassette Transporters
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