Open AccessA 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
Author(s) -
Daisuke Hagiwara,
Daisuke Miura,
Kiminori Shimizu,
Sanjoy Paul,
Ayumi Ohba,
Tohru Gonoi,
Akira Watanabe,
Katsuhiko Kamei,
Takahiro Shintani,
W. Scott MoyeRowley,
Susumu Kawamoto,
Katsuya Gomi
Publication year - 2017
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1006096
Subject(s) - aspergillus fumigatus , azole , biology , microbiology and biotechnology , itraconazole , mutant , transcription factor , chromatin immunoprecipitation , aspergillus nidulans , aspergillosis , antifungal drug , drug resistance , gene , promoter , gene expression , immunology , genetics , candida albicans , antifungal
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 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 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).