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).

A novel approach to investigate hypoxic microenvironment during rice colonization by Magnaporthe oryzae

“…And MoSRE1 is involved in regulation of the other two SREBP genes, MoSRE2 and MoSRE3 . Second, we identified homologues of the Zn 2 Cys 6 transcription factors, Upc2p and AtrR, which function to regulate ergosterol biosynthesis and hypoxia adaptation in C. albicans and A. fumigatus , respectively (MacPherson et al ., ; Hagiwara et al ., ). Lastly, M. oryzae may have alternative pathways to synthesize ergosterol.…”

Induced expression of CYP51 associated with difenoconazole resistance in the pathogenic Alternaria sect. on potato in China

“…Type II resistant isolates (the other half of the resistant isolates) were observed to contain a 6 bp insertion in the promoter region, which may be associated with DMI resistance but needs further verification. However, it is unknown whether transcription factors or CYP51 copies contribute to the over‐expression of CYP51 in our resistant isolates. These issues are worthy of further investigation.…”

Characterization of difenoconazole resistance in Lasiodiplodia theobromae from papaya in Brazil

“…Luo et al found a promoter sequence upstream of CYP51 in DMI-resistant M. fructicola isolates; 25 Ma et al found a truncated non-long terminal direct repeat long interspersed nuclear element retrotransposon leading to DMI resistance in B. jaapii; 26 and other studies have shown that tandem repeat of a transcriptional enhancer and a miniature inverted-repeat transposon were determinants of different DMI-resistant phenotypes in P. digitatum. 27,28 However, overexpression of CYP51 could also be caused by transcription factors 29 or an increased number of CYP51 copies. 30 Whether *Values followed by different letters mean significant difference at p = 0.05. these two factors were the cause of overexpression of LtCYP51 in resistant isolates will be investigated in future research.…”