A Novel Zn2-Cys6 Transcription Factor AtrR Plays a Key Role in an Azole Resistance Mechanism of Aspergillus fumigatus by Co-regulating cyp51A and cdr1B Expressions
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Successful treatment of aspergillosis caused by Aspergillus fumigatus is threatened by an increasing incidence of drug resistance. This situation is further complicated by the finding that strains resistant to azoles, the major antifungal drugs for aspergillosis, have been widely disseminated across the globe. To elucidate mechanisms underlying azole resistance, we identified a novel transcription factor that is required for normal azole resistance in Aspergillus fungi including A. fumigatus, Aspergillus oryzae, and Aspergillus nidulans. This fungal-specific Zn2-Cys6 type transcription factor AtrR was found to regulate expression of the genes related to ergosterol biosynthesis, including cyp51A that encodes a target protein of azoles. The atrR deletion mutant showed impaired growth under hypoxic conditions and attenuation of virulence in murine infection model for aspergillosis. These results were similar to the phenotypes for a mutant strain lacking SrbA that is also a direct regulator for the cyp51A gene. Notably, AtrR was responsible for the expression of cdr1B that encodes an ABC transporter related to azole resistance, whereas SrbA was not involved in the regulation. Chromatin immunoprecipitation assays indicated that AtrR directly bound both the cyp51A and cdr1B promoters. In the clinically isolated itraconazole resistant strain that harbors a mutant Cyp51A (G54E), deletion of the atrR gene resulted in a hypersensitivity to the azole drugs. Together, our results revealed that AtrR plays a pivotal role in a novel azole resistance mechanism by co-regulating the drug target (Cyp51A) and putative drug efflux pump (Cdr1B).
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Additional regulators of cyp51A expression that contribute to azole resistance in A. fumigatus include the fungal-specific transcription factors AtrR and SltA.
“Additional regulators of cyp51A expression that contribute to azole resistance in A. fumigatus include the fungal-specific transcription factors AtrR and SltA30–32.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [30]
In A. fumigatus, the fungal-specific Zn2-Cys6 type transcription factor AtrR plays a pivotal role in regulating expression of cyp51A.
“Additionally, in A. fumigatus, the fungal-specific Zn2-Cys6 type transcription factor AtrR plays a pivotal role in regulating the expression of cyp51A30,31.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [30]
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- Authors
- Hagiwara, D., Miura, D., Shimizu, K., Paul, S., Ohba, A., Gonoi, T., Watanabe, A., Kamei, K., Shintani, T., Moye-Rowley, W. S., Kawamoto, S., & Gomi, K.
- Affiliations
- Chiba University (JP)
- Tohoku University (JP)
- University of Iowa (US)
- Corresponding author
- Hagiwara, Daisuke
- Gomi, Katsuya
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-01-04
- Volume
- 13
- Issue
- 1
- Pages
- e1006096
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC5215518
- OpenAlex
- W2569875961
- Cited by
- 156
- References
- 67
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 13 · 2023: 15 · 2022: 17 · 2021: 21 · 2020: 15 · 2019: 17 · 2018: 13 · 2017: 6
- FWCI
- 10.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Joint Usage/Research Program of Medical Mycology Research Center (12-2, 13-1, 14-1, and 15-2)
- MEXT special budget for research (Controlling Aspergillosis and the related emerging mycoses)
- Cooperative Research Grant of NEKKEN (2011)
- National Bioresource project for Pathogenic Microbes
- National Institutes of Health (GM49825, AI113748)
- The Project on Controlling Aspergillosis and the Related Emerging Mycoses
- 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
- azole resistance, Aspergillus fumigatus, cyp51A, ABC transporters, ergosterol biosynthesis, itraconazole resistance, aspergillosis, drug efflux pumps, transcriptional regulation, hypoxia, virulence, antifungal resistance
- MeSH terms
- Antifungal Agents, Aspergillosis, Aspergillus fumigatus, Azoles, Cytochrome P-450 Enzyme System, Fungal Proteins, Humans, Mutation, Phenotype, Species Specificity, Transcription Factors, Gene Expression Regulation, Fungal, Itraconazole, ATP-Binding Cassette Transporters, Drug Resistance, Fungal
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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