Cited by 202Antifungal resistance and susceptibilityFungal and yeast genetics researchDrug Transport and Resistance Mechanisms

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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

Slaven, John W, Anderson, Michael J, Sanglard, Dominique, Dixon, Graham K, Bille, Jacques, Roberts, Ian S, Denning, David W·2002·Fungal Genetics and Biology

DOI 10.1016/s1087-1845(02)00016-6

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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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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
ORCID: Anderson, Michael J
Sanglard, Dominique
Roberts, Ian S
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)
DOI: 10.1016/s1087-1845(02)00016-6
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate

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