A Novel Zn-2-Cys(6) Transcription Factor AtrR Plays a Key Role in an Azole Resistance Mechanism of Aspergillus fumigatus by Coregulating cyp51A and cdr1B Expressions

Daisuke Hagiwara; Daisuke Miura; Kiminori Shimizu; Sanjoy Paul; Ayumi Ohba; Tohru Gonoi; Akira Watanabe; Katsuhiko Kamei; Takahiro Shintani; W. Scott Moye-Rowley; Susumu Kawamoto; Katsuya Gomi

doi:10.1371/journal.ppat.1006096

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A Novel Zn-2-Cys(6) Transcription Factor AtrR Plays a Key Role in an Azole Resistance Mechanism of Aspergillus fumigatus by Coregulating cyp51A and cdr1B Expressions

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A Novel Zn-2-Cys(6) Transcription Factor AtrR Plays a Key Role in an Azole Resistance Mechanism of Aspergillus fumigatus by Coregulating cyp51A and cdr1B Expressions

Daisuke Hagiwara, Daisuke Miura, Kiminori Shimizu, Sanjoy Paul, Ayumi Ohba, Tohru Gonoi, Akira Watanabe, Katsuhiko Kamei, Takahiro Shintani, W. Scott Moye-Rowley, …

PLoS pathogens, Vol.13(1), e1006096

01/01/2017

DOI: 10.1371/journal.ppat.1006096

PMCID: PMC5215518

PMID: 28052140

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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 Aspergill-us fungi including A. fumigatus, Aspergillus oryzae, and Aspergillus nidulans. This fungal-specific Zn-2-Cys(6) 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 simi-lar 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 regula-tion. Chromatin immunoprecipitation assays indicated that AtrR directly bound both the cyp51A and cdr1B promoters. In the clinically isolated itraconazole resistant strain that har-bors 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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Virology

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Title: Subtitle: A Novel Zn-2-Cys(6) Transcription Factor AtrR Plays a Key Role in an Azole Resistance Mechanism of Aspergillus fumigatus by Coregulating cyp51A and cdr1B Expressions
Creators: Daisuke Hagiwara - Chiba University
Daisuke Miura - Tohoku University
Kiminori Shimizu - Chiba University
Sanjoy Paul - Roy J. and Lucille A. Carver College of Medicine
Ayumi Ohba - Tohoku University
Tohru Gonoi - Chiba University
Akira Watanabe - Chiba University
Katsuhiko Kamei - Chiba University
Takahiro Shintani - Tohoku University
W. Scott Moye-Rowley - Roy J. and Lucille A. Carver College of Medicine
Susumu Kawamoto - Chiba University
Katsuya Gomi - Tohoku University
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.13(1), e1006096
DOI: 10.1371/journal.ppat.1006096
PMID: 28052140
PMCID: PMC5215518
NLM abbreviation: PLoS Pathog
ISSN: 1553-7366
eISSN: 1553-7374
Publisher: Public Library of Science
Number of pages: 31
Grant note: National BioResource project for Pathogenic Microbes - MEXT, Japan NEKKEN R21AI113748 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) R01GM049825 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) 17019001 / MEXT; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) 25305012 / Grants-in-Aid for Scientific Research; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Japan Society for the Promotion of Science; Grants-in-Aid for Scientific Research (KAKENHI) 12-2; 13-1; 14-1; 15-2 / Joint Usage/Research Program of Medical Mycology Research Center, Chiba University Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT); Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) GM49825; AI113748 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
Language: English
Date published: 01/01/2017
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984297510402771

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