铁载体转运蛋白 Sit1 确定抗真菌药物 VL-2397 的敏感性。,Antimicrobial Agents and Chemotherapy

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铁载体转运蛋白 Sit1 确定抗真菌药物 VL-2397 的敏感性。
Antimicrobial Agents and Chemotherapy ( IF 4.1 ) Pub Date : 2019-09-23 , DOI: 10.1128/aac.00807-19
Anna-Maria Dietl ₁ , Matthias Misslinger ₁ , Mario M Aguiar ₁ , Vasyl Ivashov ₂ , David Teis ₂ , Joachim Pfister ₃ , Clemens Decristoforo ₃ , Martin Hermann ₄ , Sean M Sullivan ₅ , Larry R Smith ₅ , Hubertus Haas ₆

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VL-2397（以前称为 ASP2397）是一种抗真菌铝螯合环状六肽，其结构类似于铁铬型铁载体，因此用铁替代铝可降低该化合物的抗真菌活性。在这里，我们发现铁铬型铁载体的输入蛋白（称为 Sit1）的失活使烟曲霉对 VL-2397 产生抗性。此外，内源性sit1基因在木糖诱导型启动子的控制下表达（以解开sit1表达与铁抑制的关系），结合C端荧光蛋白标记，证明了Sit1在质膜中的定位和木糖依赖性VL-第2397章这强调了 Sit1 介导的摄取对于 VL-2397 敏感性至关重要。在木糖诱导的sit1表达下，VL-2397在用铁替代铝后也保留了抗真菌活性，这表明VL-2397具有不依赖于细胞铝输入的抗真菌活性。对sit1表达的分析表明，铁螯合VL-2397的抗真菌活性降低是由于输入铁下调sit1表达所致。此外，我们证明铁稳态机制的缺陷可调节 VL-2397 的活性。与烟曲霉和光滑念珠菌相反，酿酒酵母对 VL-2397 抗真菌活性表现出内在耐药性。然而，烟曲霉（A. fumigatus）或其同源物光滑棒状杆菌（C. glabrata）的sit1表达导致对VL-2397的敏感性，这表明酿酒酵母的内在抗性是基于缺乏摄取，并且烟曲霉（A. fumigatus）、弯曲杆菌（C. glabrata 和 S. cerevisiae 共享 VL-2397 的细胞内靶点。

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The Siderophore Transporter Sit1 Determines Susceptibility to the Antifungal VL-2397.

VL-2397 (previously termed ASP2397) is an antifungal, aluminum-chelating cyclic hexapeptide with a structure analogous to that of ferrichrome-type siderophores, whereby replacement of aluminum by iron was shown to decrease the antifungal activity of this compound. Here, we found that inactivation of an importer for ferrichrome-type siderophores, termed Sit1, renders Aspergillus fumigatus resistant to VL-2397. Moreover, expression of the endogenous sit1 gene under the control of a xylose-inducible promoter (to uncouple sit1 expression from iron repression) combined with C-terminal tagging with a fluorescent protein demonstrated localization of Sit1 in the plasma membrane and xylose-dependent VL-2397 susceptibility. This underlines that Sit1-mediated uptake is essential for VL-2397 susceptibility. Under xylose-induced sit1 expression, VL-2397 also retained antifungal activity after replacing aluminum with iron, which demonstrates that VL-2397 bears antifungal activity independent of cellular aluminum importation. Analysis of sit1 expression indicated that the reduced antifungal activity of the iron-chelated VL-2397 is caused by downregulation of sit1 expression by the imported iron. Furthermore, we demonstrate that defects in iron homeostatic mechanisms modulate the activity of VL-2397. In contrast to A. fumigatus and Candida glabrata, Saccharomyces cerevisiae displays intrinsic resistance to VL-2397 antifungal activity. However, expression of sit1 from A. fumigatus, or its homologue from C. glabrata, resulted in susceptibility to VL-2397, which suggests that the intrinsic resistance of S. cerevisiae is based on lack of uptake and that A. fumigatus, C. glabrata, and S. cerevisiae share an intracellular target for VL-2397.

更新日期：2019-11-01

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