Biosynthesis of merochlorins - A novel class of highly active halogenated polyketide antibiotics from marine Streptomyces sp.

氯氰菊酯的生物合成 - 来自海洋链霉菌的一类新型高活性卤化聚酮化合物抗生素。

• 批准号: 215534120
• 负责人: Professor Dr. Robin Teufel
• 金额: --
• 依托单位: Center for Marine Biotechnology and Biomedicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/215534120?language=en
• 关键词: Biosynthesis; merochlorins; novel; class; highly

Marine microbes have recently emerged as an important source of chemically distinct antimicrobial agents with potential for medical applications in the treatment of infectious diseases or cancer. A plenitude of such compounds is synthesized by use of aromatic polyketide frameworks undergoing dedicated oxidative tailoring reactions, which strongly contribute to the compounds potent biological activities. Recently, some marine Streptomyces sp. were shown to produce a unique class of highly active, chlorinated polyketide antibiotics (merochlorins) that may be derived from prenylated and halogenated tetrahydroxynaphthalene precursors. Vanadium-dependent chloroperoxidases presumably catalyze the crucial cyclization and ring-expansion steps. This study aims at investigating the biosynthesis of the novel merochlorin antibiotics. The main focus of the project lies on the exploration of the biochemical steps leading to the modified tetrahydroxynaphthalene precursors, along with the examination of the proposed unprecedented chloroperoxidase-catalyzed macrocyclization and ring-formation/expansion reactions. Systematic gene inactivation, in vitro studies of heterologous proteins and their catalytic features, site-directed mutagenesis, and X-ray crystallography will be applied to functionally assign and characterize involved proteins and to expose the underlying reaction mechanisms, with the ultimate goal to establish biosynthetic pipelines for biological evaluation in antibiotic screens.

海洋微生物最近已成为化学上独特的抗菌剂的重要来源，具有在治疗传染病或癌症的医疗应用中的潜力。许多此类化合物是通过使用芳香族聚酮化合物骨架进行专门的氧化修饰反应合成的，这极大地促进了化合物的有效生物活性。最近，一些海洋链霉菌。已被证明可以产生一类独特的高活性氯化聚酮化合物抗生素（部分二氯林），该抗生素可能源自异戊二烯化和卤化四羟基萘前体。钒依赖性氯过氧化物酶可能催化关键的环化和扩环步骤。本研究旨在研究新型二氯甲烷抗生素的生物合成。该项目的主要重点在于探索导致改性四羟基萘前体的生化步骤，以及对所提出的前所未有的氯过氧化物酶催化的大环化和成环/扩张反应的检查。系统性基因失活、异源蛋白及其催化特征的体外研究、定点突变和X射线晶体学将用于对相关蛋白进行功能分配和表征，并揭示潜在的反应机制，最终目标是建立用于抗生素筛选中生物评价的生物合成管道。