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.

项目摘要 /摘要由稳定的碳磷（C-P）键的存在定义的磷酸是一种不足具有生物医学承诺的化合物组。此类中最有趣，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天然产品。伟大的生物元素磷酸和磷酸酸的Cal潜力源于（1） cial应用，（2）细胞靶标和作用方式的巨大多样性（3）可用性允许轻松发现和表征的研究工具，（4）新颖，未表征的可靠储层班级成员，以及（5）特征的不寻常生物合成途径增强和表现我们对基本生物化学的了解。该研究项目利用这些功能，专注于具有有用的生物活性和有趣化学物质的阳极细菌的膦酸酯天然产物特征以及新型磷酸盐的发现。该项目的长期目标包括阐明选定磷酸盐和开发生物活性C-P化合物的有效表征和生产工具。具体拟议的融资期的目的是：（1）表征两种杂交多重力的生物合成。潮汐/磷酸天然产物，（2）表征罕见的H磷酸的生物合成，（3）特征不寻常的分支链磷酸链和（4）开发的生物合成的变化异源表达宿主，有助于发现和生产新型磷酸天然产物。