利用细胞色素P450单加氧酶理性改造抗生素结构的研究

项目名称： 利用细胞色素P450单加氧酶理性改造抗生素结构的研究

项目编号： No.31300075

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 张伟

作者单位： 中国科学院青岛生物能源与过程研究所

项目金额： 25万元

中文摘要： 大环内酯属于I型聚酮类化合物，具有良好的广谱抗菌活性，是临床应用最广泛的抗菌药物之一。目前具有14元环大环内酯类抗生素耐药性的细菌已越发普遍，而16元环大环内酯类抗生素如泰乐霉素与麦新米星对许多耐药菌显示出良好活性，但却分别因药代动力学缺陷和神经毒性导致其应用受限。基于两类抗生素化学结构相似，生物合成途径和基因簇同源性高的特点，本项目前期研究已经证实麦新米星基因簇中的细胞色素P450单加氧酶MycG可以在体外催化泰乐霉素衍生物descomycin形成羟基化和环氧化产物。因此，我们提出通过生物合成途径重组技术将P450 MycG整合到泰乐霉素产生菌弗氏链霉菌染色体上进行异源表达，对泰乐霉素类抗生素的化学结构进行改造，理性地设计和创造具有更好成药性和更低毒性的新型抗生素，为开发新的抗耐药菌或其他疾病的抗生素提供新思路。本研究对新活性天然产物的发掘和现有抗生素的改良也具有重要的理论和应用价值。

中文关键词： 细胞色素单加氧酶P450；大环内酯；MycG；生物合成途径重组；泰乐菌素

英文摘要： The macrolide antibiotics belong to type I polyketide natural products. Due to excellent wide-spectrum antibacterial activity, this class of antibiotics has been one of the most widely used antimicrobial agents in clinical applications. Nowadays, bacterial strains resistant to 14-membered ring macrolide antibiotics are becoming more and more common, while the 16-membered ring macrolide antibiotics such as tylosin and mycinamicin display good activity against many drug-resistant pathogens. However, tylosin's defects in pharmakinetics and mycinamicin's neurotoxicity have limited further application of these two macrolides. In comparison, these two antibiotics have similar chemical structures, biosynthetic gene clusters and hence biosynthetic pathways. Our preliminary study has demonstrated that the cytochrome P450 monooxygenase MycG from mycinamicin gene cluster is capable of converting the tylosin derivative descomycin into hydroxylated and epoxidized products. Based on the structural analysis of the new products, they may possess the characteristics of enhanced antibacterial activity and reduced neurotoxicity. Thus, in this project we propose to introduce the MycG encoding gene to the chromosome of tylosin producing strain Streptomyces fradiae. It is anticipated that the heterologous expression of MycG would rep

英文关键词： Cytochrome P450；macrolide antibiotics；MycG；Biosynthetic Pathway Reprogramming；tylosin