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Genomics-Accelerated Discovery and Biosynthesis of Phosphonic Acid Natural Products

基因组学-膦酸天然产物的加速发现和生物合成

基本信息

批准号：
10665605
负责人：
Kou-San Ju
金额：
$ 30.43万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665605
关键词：
Acceleration Actinobacteria class Acute Agriculture Amination Amino Acids Anabolism Antibiotics Antimalarials Antimicrobial Resistance Arginine Biochemical Biochemistry Biological Biotechnology Carbon Chemicals Classification Classification Scheme Communicable Diseases DNA Sequence Development Dwarfism Engineering Enzymatic Biochemistry Enzymes Esters Family Future Gene Cluster Genetic Genetic Variation Genome Genomics Goals Health Heme Human Hydroxylation Infection Knowledge Ligase Ligation Medicine Metabolic Mining Modification Molecular Molecular Target Natural Products Nature Outcome Oxidoreductase Pathway interactions Peptides Phosphonic Acids Phosphorus Property Research Route Source Stream Substrate Specificity System Transfer RNA Viral antimicrobial commercialization drug development effective therapy genomic data grasp human mortality improved innovation insight interest microbial microbial genome microbial genomics mimicry multi-drug resistant pathogen novel pharmacophore phosphonate public repository response

项目摘要

PROJECT SUMMARY Microbial phosphonic acids are a class of understudied natural products with significant utility in medicine. The antimicrobial, antiviral, and antimalarial activity of many useful phosphonic acids derives from potent and specific inhibition of metabolic enzymes through chemical mimicry of their natural substrates. These properties, along with the trove of novel biosynthetic gene clusters encoded within microbial genomic datasets, highlight their potential of phosphonic acid natural products new antimicrobials. In this project we focus our efforts on realizing their genomic potential of these compounds by establishing fundamental genetic and biochemical principles that define their biosynthetic and bioactivity landscape. Filling these gaps in knowledge will provide a systems-level understanding of natural product biosynthesis necessary to improve discovery and engineering of new phosphonic acids. Specifically, we investigate three recently discovered phosphonic acid peptides to uncover unusual hydroxylation, reduction, amination, and amino acid ligation enzymes, and the molecular basis of their antimicrobial activity. We expand and refine the framework for phosphonic acid natural product genomics through the isolation of new compounds from cryptic gene clusters, discovery of new pathways and enzymes for C-P bond formation, and the development of a classification scheme to improve prediction of phosphonic acid gene clusters and their chemical products.

项目总结