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.
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.
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DOI：
10.1371/journal.ppat.1006096
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发表时间：
2017-01
期刊：
影响因子：
6.7
通讯作者：
Gomi K
中科院分区：
文献类型：
--
作者：
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
由烟曲霉引起的曲霉病的成功治疗受到日益增加的耐药性发生率的威胁。这种情况进一步复杂的发现，耐唑类，曲霉病的主要抗真菌药物，菌株已广泛传播到地球仪。为了阐明唑类耐药的机制，我们鉴定了一种新的转录因子，该因子是曲霉属真菌（包括曲霉属真菌）正常唑类耐药所必需的。烟曲霉、黑曲霉和构巢曲霉。发现该真菌特异性Zn 2-Cys 6型转录因子AtrR调节麦角甾醇生物合成相关基因的表达，包括编码唑类靶蛋白的cyp 51 A。atrR缺失突变体在缺氧条件下生长受损，在曲霉病小鼠感染模型中毒力减弱。这些结果与缺乏SrbA的突变株的表型相似，SrbA也是cyp 51 A基因的直接调节因子。值得注意的是，AtrR负责编码与唑类耐药相关的ABC转运蛋白的cdr 1B的表达，而SrbA不参与调节。染色质免疫沉淀试验表明，AtrR直接绑定cyp 51 A和cdr 1B启动子。在临床分离的伊曲康唑耐药菌株中，突变Cyp 51 A（G54 E），atrR基因的缺失导致对唑类药物的超敏反应。总之，我们的研究结果表明，AtrR通过共调节药物靶点（Cyp 51 A）和假定的药物外排泵（Cdr 1B）在一种新的唑类耐药机制中起着关键作用。慢性病患者的生存率提高，导致真菌感染性疾病病例增加。这部分是由于大量的免疫功能低下的患者。同时，抗真菌药物的目录仍然相当有限，耐药菌株的出现越来越普遍。丝状真菌烟曲霉是深部曲霉病的主要致病菌。对于这种真菌，对唑类药物（最常用的治疗曲霉病的药物）的耐药性已显示出与死亡率升高相关的惊人增加。我们知道相对较少的分子细节支撑唑耐药在A。除了目标酶的改变之外，烟曲霉。在这里，我们确定并表征了一种新的转录因子AtrR，该转录因子是该真菌以及其他曲霉属真菌（如Aspergillusspermatum和Aspergillusnidulans）中野生型唑类耐药性所需的。我们发现AtrR共调节靶点和泵，这两者对于唑类耐药都是必不可少的。更重要的是，atrR基因的缺失可以使临床分离的多唑耐药菌株敏感，并在小鼠模型中表现出毒力缺陷。这种克服现有耐药突变的成功为曲霉病的预防和治疗提供了新的途径。
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). Better survival of chronically ill patients has produced an increased number of cases involving fungal infectious disease. This is partly due to a larger number of immunocompromised patients. Meanwhile, the catalogue of antifungal drugs remains quite limited and the appearance of resistant isolates is becoming more common. The filamentous fungus Aspergillus fumigatus is the main causative pathogen for deep-seated aspergillosis. For this fungus, resistance to azoles, which are the most commonly utilized drug for treatment of aspergillosis, has exhibited an alarming increase linked with elevated mortality. We know relatively little of the molecular details underpinning azole resistance in A. fumigatus other than alterations in the target enzyme. Here, 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. More importantly, deletion of the atrR gene could sensitize a clinically isolated multi-azole resistant strain and exhibited a virulence defect in a mouse model. This success in overcoming an existing resistance mutation provides a new avenue for the prevention and treatment of aspergillosis.
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