A Novel Zn2-Cys6Transcription Factor AtrR Plays a Key Role in an Azole Resistance Mechanism of Aspergillus fumigatus by Co-regulating 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

研究成果: Article査読

61 被引用数 (Scopus)

抄録

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-Cys6type 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).

本文言語English
論文番号e1006096
ジャーナルPLoS Pathogens
13
1
DOI
出版ステータスPublished - 2017 1

ASJC Scopus subject areas

  • 寄生虫科
  • 微生物学
  • 免疫学
  • 分子生物学
  • 遺伝学
  • ウイルス学

フィンガープリント

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