title: 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.
abstract: 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).
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Daisuke
authors.identifier: 0000-0003-1382-3914
authors.initials: D
authors.lastname: Hagiwara
authors.affiliation: Department of Bioindustrial Informatics and Genomics, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miura
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Paul
authors.affiliation: Department of Bioindustrial Informatics and Genomics, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ohba
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Gonoi
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Katsuhiko
authors.identifier: 0000-0002-6067-9049
authors.initials: K
authors.lastname: Kamei
authors.affiliation: Department of Bioindustrial Informatics and Genomics, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
authors.forename: Takahiro
authors.identifier: 0000-0001-6630-5892
authors.initials: T
authors.lastname: Shintani
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: W Scott
authors.identifier: 0000-0002-7163-1120
authors.initials: WS
authors.lastname: Moye-Rowley
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Susumu
authors.identifier: 0000-0002-7297-1717
authors.initials: S
authors.lastname: Kawamoto
authors.affiliation: Department of Bioindustrial Informatics and Genomics, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Gomi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000235:genetics*; D001393:Azoles / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D009154:Mutation; D010641:Phenotype; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D014157:Transcription Factors; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus