Discovery, biosynthesis and bioactivity of phosphonic acid natural products

项目摘要/摘要 由稳定的碳-磷(C-P)键的存在定义的磷酸是一种未被开发的 一组具有生物医学前景的化合物。这个班级中最有趣和最有用的成员有 天然产品，包括具有强大的抗菌、抗真菌和抗病毒活性的产品。伟大的生物医学- 膦酸和膦酸的CAL潜力，源于(1)在临床和通信方面的已证实的记录。 社会应用，(2)细胞目标和行动模式的巨大多样性(3)提供一套 研究工具，可方便地发现和表征，(4)已证实的新的、未表征的储藏库 这一类的成员，以及(5)不寻常的生物合成途径，其特征被增强和超越- 使我们的基础生物化学知识枯竭。本研究项目利用了这些特点， 关注从放线杆菌中提取的具有有用生物活性和有趣化学成分的天然产物 特征，以及新的磷酸盐的发现。该项目的长期目标包括澄清 从基因、生物合成途径、抗性机制和生物活性等方面对所选的磷酸盐和 开发有效表征和生产生物活性碳-磷化合物的工具。具体的 拟议资助期的目标是：(1)表征两种杂交聚酮的生物合成- 潮汐/磷酸盐天然产物，(2)稀有H-磷酸盐生物合成的表征，(3)特性- 一种特殊支链膦酸酯的生物合成及优化研究 异源表达宿主，以帮助发现和生产新的磷酸天然产物。

Project Summary / Abstract Phosphonic acids, defined by the presence of stable carbon-phosphorus (C-P) bonds, are an underexploited group of compounds with biomedical promise. Some the most interesting and useful members of this class are natural products, including ones with potent antibacterial, antifungal, and antiviral activities. The great biomedi- cal potential of phosphonic and phosphinic acids, stems from (1) a proven track record in clinical and commer- cial applications, (2) an immense diversity of cellular targets and modes of action (3) availability of a suite of research tools that allow facile discovery and characterization, (4) a proven reservoir of novel, uncharacterized members of the class, and (5) unusual biosynthetic pathways whose characterization has enhanced and ex- panded our knowledge of fundamental biochemistry. This research project takes advantage of these features, focusing on phosphonate natural products from actinobacteria with useful bioactivities and interesting chemical features, as well as the discovery of novel phosphonates. The long-term goals of the project include elucidation of the genes, biosynthetic pathways, resistance mechanisms and bioactivities of selected phosphonates and development of tools for efficient characterization and production of bioactive C-P compounds. The specific aims for the proposed funding period are: (1) characterization of the biosynthesis of two hybrid polyke- tide/phosphonate natural products, (2) characterization of the biosynthesis of a rare H-phosphinate, (3) charac- terization of the biosynthesis of an unusual branched chain phosphonate and (4) development an optimized heterologous expression host to aid the discovery and production of novel phosphonic acid natural products.