| RRC ID |
52789
|
| 著者 |
Hagiwara D, Miura D, Shimizu K, Paul S, Ohba A, Gonoi T, Watanabe A, Kamei K, Shintani T, Moye-Rowley WS, Kawamoto S, Gomi K.
|
| タイトル |
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.
|
| ジャーナル |
PLoS Pathog
|
| 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).
|
| 巻・号 |
13(1)
|
| ページ |
e1006096
|
| 公開日 |
2017-1-1
|
| DOI |
10.1371/journal.ppat.1006096
|
| PII |
PPATHOGENS-D-16-01104
|
| PMID |
28052140
|
| PMC |
PMC5215518
|
| MeSH |
ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / metabolism
Antifungal Agents / pharmacology*
Aspergillosis / microbiology*
Aspergillus fumigatus / drug effects
Aspergillus fumigatus / genetics*
Azoles / pharmacology
Cytochrome P-450 Enzyme System / genetics
Cytochrome P-450 Enzyme System / metabolism
Drug Resistance, Fungal
Fungal Proteins / genetics*
Fungal Proteins / metabolism
Gene Expression Regulation, Fungal*
Humans
Itraconazole / pharmacology
Mutation
Phenotype
Species Specificity
Transcription Factors / genetics
Transcription Factors / metabolism
|
| IF |
6.218
|
| 引用数 |
38
|
| リソース情報 |
| 病原真核微生物 |
病原真菌： IFM 61567, IFM 54229 (= Af293 ) |
