Discovery, biosynthesis and bioactivity of phosphonic acid natural products

项目概要/摘要 膦酸，由稳定的碳-磷（C-P）键的存在定义，是一种开发不足的 具有生物医学前景的化合物。这个类中一些最有趣和最有用的成员是 天然产物，包括具有强效抗菌、抗真菌和抗病毒活性的天然产物。伟大的生物地- 膦酸和次膦酸的潜在用途，源于（1）在临床和商业上的良好记录， （2）细胞靶点和作用模式的巨大多样性（3）一套 研究工具，使容易发现和表征，（4）一个证明水库的新的，未表征 类的成员，和（5）不寻常的生物合成途径，其特征已增强和前， 利用了我们的基础生物化学知识本研究项目利用这些特点， 重点研究放线菌中具有生物活性和化学性质的膦酸盐天然产物 功能，以及新的膦酸盐的发现。该项目的长期目标包括阐明 基因，生物合成途径，抗性机制和选定的膦酸盐的生物活性， 开发用于有效表征和生产生物活性C-P化合物的工具。具体 拟议的资助期的目标是：（1）两种杂交聚乙二醇的生物合成特性， （2）稀有H-次膦酸盐生物合成的表征，（3）特征- 一种特殊的支链膦酸酯的生物合成方法;（4）开发一种优化的 异源表达宿主以帮助发现和生产新的膦酸天然产物。

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.