Discovery, biosynthesis and bioactivity of phosphonic acid natural products

膦酸天然产物的发现、生物合成及生物活性

基本信息

批准号：
9900830
负责人：
WILLIAM W METCALF
金额：
$ 36.05万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900830
关键词：
Actinobacteria class Anabolism Anti-Bacterial Agents Antifungal Agents Antimalarials Antiviral Agents Bacteria Biochemistry Biomedical Engineering Cancer cell line Candida Carbon Chemical Structure Chemicals Complex Development Enzymes Funding Gene Cluster Genes Genetic Goals Hybrids Knowledge Medical Molecular Natural Products Organism Pathway interactions Performance Phosphinic Acids Phosphonic Acids Phosphorus Physical condensation Production Property Reaction Research Research Project Grants Resistance Salvelinus Series Streptomyces Structure Testing Thiamine Pyrophosphate Validation carbon skeleton cellular targeting clinical application commercial application fosmidomycin fungus insight member mutant novel phosphonate phosphorus compounds polyketide synthase resistance mechanism screening program stem tool tool development yeast two hybrid system

项目摘要

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.

项目概要/摘要膦酸由稳定的碳-磷 (C-P) 键的存在定义，是一种尚未充分开发的化合物一组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品，包括具有有效抗菌、抗真菌和抗病毒活性的产品。伟大的生物医学膦酸和次膦酸的钙潜力源于 (1) 在临床和商业方面的良好记录社会应用，（2）细胞靶点和作用模式的巨大多样性（3）一套可用性允许轻松发现和表征的研究工具，（4）经过验证的新颖的、未表征的储库该类的成员，以及（5）不寻常的生物合成途径，其特征已增强并已消除扩展了我们的基础生物化学知识。该研究项目利用了这些特征，专注于放线菌中具有有用生物活性和有趣化学物质的膦酸盐天然产物特征，以及新型膦酸盐的发现。该项目的长期目标包括阐明所选膦酸盐的基因、生物合成途径、耐药机制和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。具体的拟议资助期的目标是：（1）表征两种杂化聚酮的生物合成潮汐/膦酸盐天然产物，(2) 稀有 H-次膦酸盐生物合成的表征，(3) 特征一种不寻常的支链膦酸盐的生物合成的实现以及（4）开发一种优化的异源表达宿主有助于发现和生产新型膦酸天然产物。