机制基础 pH 依赖性 5-氟胞嘧啶在烟曲霉中的耐药性。
Mechanistic Basis of pH-Dependent 5-Flucytosine Resistance in Aspergillus fumigatus.
机构信息
Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Core Technology Facility, Manchester, United Kingdom.
Division of Molecular Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
出版信息
Antimicrob Agents Chemother. 2018 May 25;62(6). doi: 10.1128/AAC.02593-17. Print 2018 Jun.
The antifungal drug 5-flucytosine (5FC), a derivative of the nucleobase cytosine, is licensed for the treatment of fungal diseases; however, it is rarely used as a monotherapeutic to treat infection. Despite being potent against other fungal pathogens, 5FC has limited activity against when standard assays are used to determine susceptibility. However, in modified assays where the pH is set to pH 5, the activity of 5FC increases significantly. Here we provide evidence that , a gene that encodes a purine-cytosine permease orthologous to known 5FC importers, is downregulated at pH 7 and is the primary factor responsible for the low efficacy of 5FC at pH 7. We also uncover two transcriptional regulators that are responsible for the repression of and, consequently, mediators of 5FC resistance, the CCAAT binding complex (CBC) and the pH regulatory protein PacC. We propose that the activity of 5FC might be enhanced by the perturbation of factors that repress expression, such as PacC or other components of the pH-sensing machinery.
抗真菌药物 5-氟胞嘧啶（5FC）是碱基胞嘧啶的衍生物，已获得许可用于治疗真菌感染；然而，它很少作为单一药物用于治疗 感染。尽管 5FC 对其他真菌病原体具有很强的活性，但在用于确定敏感性的标准 检测中，它对 的活性有限。然而，在 pH 值设定为 pH 5 的改良 检测中，5FC 的活性显著增加。在这里，我们提供的证据表明，编码与已知 5FC 进口器同源的嘌呤-胞嘧啶渗透酶的 基因在 pH 7 时下调，是 5FC 在 pH 7 时疗效低的主要因素。我们还发现了两个转录调节因子，它们负责 的抑制，以及 5FC 耐药的介体，CCAAT 结合复合物（CBC）和 pH 调节蛋白 PacC。我们提出，通过干扰抑制 表达的因素（如 PacC 或其他 pH 感应机制的成分），可能会增强 5FC 的活性。
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