A Hyperactive Form of the Zinc Cluster Transcription Factor Stb5 Causes YOR1 Overexpression and Beauvericin Resistance in Candida albicans
A Hyperactive Form of the Zinc Cluster Transcription Factor Stb5 Causes YOR1 Overexpression and Beauvericin Resistance in Candida albicans
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DOI：
10.1128/aac.01655-18
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发表时间：
2018-12-01
影响因子：
4.9
通讯作者：
Morschhaeuser, Joachim
中科院分区：
文献类型：
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作者：
Ramirez-Zavala, Bernardo;Manz, Hannah;Morschhaeuser, Joachim
锌簇转录因子Mrr 1、Tac 1和Upc 2的功能获得性突变导致其靶基因的组成性过表达，是致病性酵母菌白色念珠菌对氟康唑耐药的常见原因。在这项研究中，我们表明，另一个锌簇转录因子，Stb 5，赋予抗性的天然化合物白僵菌素通过过表达的YOR 1，编码的ATP结合盒转运超家族的外排泵。最近发现，白僵菌素可增强唑类药物抗念珠菌的活性。白色念珠菌。虽然Yor 1在C. Stb 5介导的YOR 1过表达减弱了氟康唑-白僵菌素联合的协同作用，从而增强了白僵菌素处理的C.白色念珠菌细胞。Stb 5介导的YOR 1过表达也抑制了对菌丝生长的抑制，这是C.白僵菌素的白色念珠菌因此，激活Stb 5中的突变，导致组成型YOR 1过表达，可能使C.白念珠菌获得对白僵菌素的抗性，从而克服对唑类药物的敏化和由该化合物引起的形态发生的抑制。
Gain-of-function mutations in the zinc cluster transcription factors Mrr1, Tac1, and Upc2, which result in constitutive overexpression of their target genes, are a frequent cause of fluconazole resistance in the pathogenic yeast Candida albicans. In this study, we show that an activated form of another zinc cluster transcription factor, Stb5, confers resistance to the natural compound beauvericin via the overexpression of YOR1, encoding an efflux pump of the ATP-binding cassette transporter superfamily. Beauvericin was recently shown to potentiate the activity of azole drugs against C. albicans. Although Yor1 did not contribute to fluconazole resistance when C. albicans cells were treated with the drug alone, Stb5-mediated YOR1 overexpression diminished the synergistic effect of the fluconazole-beauvericin combination, thereby enhancing fluconazole resistance in beauvericin-treated C. albicans cells. Stb5-mediated YOR1 overexpression also suppressed the inhibition of hyphal growth, an important virulence trait of C. albicans, by beauvericin. Therefore, activating mutations in Stb5, which result in constitutive YOR1 overexpression, may enable C. albicans to acquire resistance to beauvericin and thereby overcome both the sensitization to azole drugs and the inhibition of morphogenesis caused by this compound.