异苯并呋喃聚酮抗生素的生物合成机制研究

The extracted metabolites of Paecilomyces variotii are known to possess a strong inhibition activity against multiple pathogens.Jung et.al. have reported the isolation of three new isobenzofuran derivatives, which can be used as potential drug leads for antibiotic development. Paecilomyces variotii is a significant conditional pathogen, which could result in lung infection of human with hypoimmunity. To our best, there is no known literature on the biosynthetic origin of isobenzofuran derivatives, although isobenzofuran derivatives are pretty important in medicinal field and organic synthesis. We are prone to amplify a conservative fragment based on bioinformatic analysis, which can be used as the probe targeting the producing gene cluster. We also want to conduct some combinatorial biosynthesis via using DNA shuffling. The target gene cluster can be put under a strong promoter and expressed in a hererologous host strain to improve the production efficiency of new isobenzofuran derivatives. Furthermore, we want to carry out a comparative microbiologic study via using deep sequencing, which can be used in identification of new antibiotic targeting gene. Last but not least, we want to set up a drug screening model which can be used in the development of new drugs against infection of Paecilomyces variotii.

宛氏拟青霉菌的代谢产物对多种病原细菌表现出强烈的抑菌活性，最近从中新分离得到的三个活性成分，具备较大的药用研究价值，其结构为异苯并呋喃类衍生物。异苯并呋喃类衍生物尽管十分重要，但相关的生物合成机制仍然没有得到阐明。我们拟设计保守探针序列钓取目标化合物的合成基因簇，进一步通过DNA shuffling进行组合生物合成的研究，并将目标基因簇转移到异源表达宿主中，通过发酵途径高产活性更好的异苯并呋喃衍生物。宛氏拟青霉同时又是一种条件致病菌，当人免疫力低下时，可引起肺部感染。因此，更进一步地，我们拟通过深度测序对宛氏拟青霉开展比较病原微生物学方面的研究，引导发现抗生素的新作用靶点基因，并用于药物筛选，寻找治疗宛氏拟青霉感染的新药。

宛氏拟青霉菌的代谢产物对多种耐药病原细菌表现出较好的抑菌活性，我们通过活性导向的策略对其进行了深入研究，通过琼脂抑菌斑试验和高效液相色谱定位活性成分，结合高分辨质谱以及HPLC-MS 分析，正在尝试提高目标活性成分的产量并进行分离纯化。.我们还研究了8位鸟嘌呤氧化性加合物对于DNA B-Z转换的影响，发现在12个碱基的序列中中有一个鸟嘌呤被氧化，即可明显促进DNA从右手螺旋到左手螺旋的转化。由于8位氧化鸟嘌呤是活性氧自由基如单线态氧、羟自由基等进攻DNA中的鸟嘌呤碱基第8位碳原子而产生的一种氧化损伤，在细胞中非常常见，具有致DNA突变作用。.通过本项目的运行，在国际SCI期刊上发表论文四篇，获授权专利1项，在申请专利1项，培养硕士研究生1名，博士研究生1名。

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