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Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate
Abstract
Aspergillus fumigatus is the most frequent causative agent of invasive aspergillosis. Itraconazole became available in 1990 to treat invasive aspergillosis, but instances of resistance have now been described. Drug efflux was a proposed mechanism in one itraconazole resistant clinical isolate (AF72) which accumulates low levels of the drug. Drug efflux in fungi can be mediated by ATP-binding cassette transporter (ABCT) genes, such as CDR1 in Candida albicans. Using a probe derived from CDR1, a gene, atrF, was cloned from A. fumigatus. The atrF gene product (AtrF) is 1547 amino acids long and has characteristic multidrug resistance motifs. Dot blot analysis revealed that AF72 has approximately 5-fold higher levels of atrF mRNA than susceptible isolates AF10 and H06-03 in cultures with sub-minimum inhibitory concentration (sub-MIC) levels of itraconazole. atrF is the first ABCT gene cloned from A. fumigatus, whose overexpression is correlated with itraconazole resistance.
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“Overexpression of multidrug efflux transporters also mediates azole resistance in other fungal pathogens, with the major players being the ABC transporters Afr1 and AtrF for C. neoformans and A. fumigatus, respectively60,61.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [60]
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Metadata
- Authors
- Slaven, J. W., Anderson, M. J., Sanglard, D., Dixon, G. K., Bille, J., Roberts, I. S., & Denning, D. W.
- Affiliations
- University of Manchester (GB)
- Centre Hospitalier Universitaire Vaudois (CH)
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Denning, David W
- Venue
- Fungal Genetics and Biology
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 36
- Issue
- 3
- Pages
- 199-206
- ISSN
- 1087-1845 (ISSN-L)
- OpenAlex
- W2097302864
- Cited by
- 202
- References
- 45
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 8 · 2019: 10 · 2018: 7 · 2017: 14 · 2016: 12 · 2015: 8 · 2014: 14 · 2013: 12 · 2012: 7
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Fungal Genetics and Biology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Medical Research Council
- 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
- Aspergillus fumigatus, ABC transporters, itraconazole resistance, drug efflux, multidrug resistance, gene overexpression, invasive aspergillosis, antifungal resistance
- MeSH terms
- Amino Acid Sequence, Antifungal Agents, Aspergillus fumigatus, Base Sequence, Cloning, Molecular, Drug Resistance, Microbial, Microbial Sensitivity Tests, Molecular Sequence Data, Immunoblotting, Gene Expression Regulation, Fungal, Itraconazole, ATP-Binding Cassette Transporters
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