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).
Highlights
Aspergillosis is one of the most common infectious diseases by mold, with Aspergillus fumigatus being the most frequently causative fungus with high mortality
We identified and characterized a novel transcription factor AtrR that is required for wild-type azole resistance in this fungus as well as other Aspergillus fungi, such as Aspergillus oryzae and Aspergillus nidulans
We discovered that AtrR co-regulates the target and pump, both of which are essential for azole resistance
Summary
Aspergillosis is one of the most common infectious diseases by mold, with Aspergillus fumigatus being the most frequently causative fungus with high mortality (more than 60%). Further worsening the outlook for successful antifungal therapy, azole resistant A. fumigatus strains have been found with increasing incidence worldwide [1,2]. Azoles are an essential antifungal drug for therapy for chronic aspergillosis. Azole resistant A. fumigatus strains exhibit a poor clinical outcome [3]. The experiment using a clinical azole-resistant isolate revealed a potential clinical relevance of AtrR. Our findings provide the first direct evidence that AtrR serves as a critical coordinator of both ergosterol biosynthesis and levels of a plasma membrane ABC transporter that can efflux azole drugs, the major antifungal drug in current use against pathogenic fungi
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