SREBP-Dependent Triazole Susceptibility in Aspergillus fumigatus Is Mediated through Direct Transcriptional Regulation of erg11A (cyp51A)
SREBP-Dependent Triazole Susceptibility in Aspergillus fumigatus Is Mediated through Direct Transcriptional Regulation of erg11A (cyp51A)
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DOI：
10.1128/aac.05027-11
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发表时间：
2012-01-01
影响因子：
4.9
通讯作者：
Cramer, Robert A.
中科院分区：
文献类型：
--
作者：
Blosser, Sara J.;Cramer, Robert A.
随着三氮唑类抗真菌药物在侵袭性烟曲霉菌感染中的耐药性日益普遍，了解烟曲霉菌耐药机制的必要性日益增加。曲霉中存在两个erg11(Cyp51)基因。假设是为了解释这种霉菌对三唑氟康唑(FLC)的固有抗药性。最近，发现烟曲霉类固醇调节元件结合蛋白(SREBP)家族转录调控因子的零突变Delta srbA株对FLC和伏立康唑(VCZ)的敏感性增加。在这项研究中，我们研究了在没有srbA的情况下，导致观察到的烟曲霉菌三唑敏感性增加的机制。我们观察到Delta srbA株对FLC和VCZ的反应中erg11A转录本显著减少。Erg11B的转录水平也降低了，但没有下降到erg11A的程度。有趣的是，erg11A转录水平在延长VCZ暴露时增加，但不增加FLC。在Delta srbA菌株中构建erg11A条件表达菌株能够恢复erg11A转录水平，从而将野生型MICs恢复到三唑FLC。随着erg11A转录本水平的增加，VCZ MIC也部分恢复；然而，与野生型相比，总麦角固醇水平仍然显著降低。Erg11A条件菌株的诱导不能恢复Delta srbA菌株的缺氧生长缺陷。综上所述，我们的结果显示了srbA介导的调节烟曲霉菌麦角固醇生物合成和三氮唑类药物相互作用的关键作用，这可能具有临床意义。
As triazole antifungal drug resistance during invasive Aspergillus fumigatus infection has become more prevalent, the need to understand mechanisms of resistance in A. fumigatus has increased. The presence of two erg11 (cyp51) genes in Aspergillus spp. is hypothesized to account for the inherent resistance of this mold to the triazole fluconazole (FLC). Recently, an A. fumigatus null mutant of a transcriptional regulator in the sterol regulatory element binding protein (SREBP) family, the Delta srbA strain, was found to have increased susceptibility to FLC and voriconazole (VCZ). In this study, we examined the mechanism engendering the observed increase in A. fumigatus triazole susceptibility in the absence of SrbA. We observed a significant reduction in the erg11A transcript in the Delta srbA strain in response to FLC and VCZ. Transcript levels of erg11B were also reduced but not to the extent of erg11A. Interestingly, erg11A transcript levels increased upon extended VCZ, but not FLC, exposure. Construction of an erg11A conditional expression strain in the Delta srbA strain was able to restore erg11A transcript levels and, consequently, wildtype MICs to the triazole FLC. The VCZ MIC was also partially restored upon increased erg11A transcript levels; however, total ergosterol levels remained significantly reduced compared to those of the wild type. Induction of the erg11A conditional strain did not restore the hypoxia growth defect of the Delta srbA strain. Taken together, our results demonstrate a critical role for SrbA-mediated regulation of ergosterol biosynthesis and triazole drug interactions in A. fumigatus that may have clinical importance.