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Natural Product Genome Mining

天然产物基因组挖掘

基本信息

批准号：
10462325
负责人：
PAUL R JENSEN
金额：
$ 4.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10462325
关键词：
Address Anabolism Antibiotics Bacteria Bioinformatics Biological Chemicals Chemistry Clinical Cloning Collaborations Collection Communicable Diseases Crude Extracts DNA Development Engineering Environment Enzymes Evolution Expeditions Fractionation Future Gene Cluster Genes Genetic Genetic Transcription Genome Genomics Goals Human Hybrids Knowledge Laboratories Lactones Lead Learning Link Malignant neoplasm of brain Marine Sediment Medicine Metagenomics Methods Microbe Microbiology Mining Modeling Modernization Natural Products Natural Products Chemistry Nature Oceanography Oceans Orphan Peptide Hydrolases Pharmaceutical Preparations Proteasome Inhibitor Research Resources Sampling Science Signaling Molecule Synthetic Genes Taxon Techniques Testing Time Vanadium Virulence Virulence Factors antimicrobial base chemical group comparative genomics deep ocean design drug discovery emerging antibiotic resistance experimental study gene synthesis human disease innovation insight isoprenoid metagenome meter microbial microbial genome novel novel therapeutics phase III trial programs public health relevance resistance gene salinosporamide A screening program small molecule synthetic biology tool

项目摘要

Project Summary / Abstract Natural products continue to provide important drug leads in medicine. While the majority of clinical antibiotics are derived from bacterial natural products, the emergence of antibiotic resistance emphasizes the need to discover new antimicrobial leads. This renewal application builds upon a productive collaboration between the Jensen (microbiology/bioinformatics) and Moore (biosynthesis/natural products chemistry) laboratories to address this need through the mining of microbial genomes and metagenomes for new bioactive compounds. We have prioritized two diverse groups of chemically gifted marine bacteria for study from a collection of >10,000 strains collected across the world’s oceans. We continue our efforts with the obligate marine actinomycete Salinispora, which produces the potent proteasome inhibitor salinosporamide A (Marizomib) that is presently in phase III trials to treat brain cancer. Here we capitalize on the recent identification of six new Salinispora species and 99 new genomes to expand our efforts in this unique taxon. We further expand our genome mining efforts to include the MAR4 lineage, a second chemically gifted group of marine bacteria for which we are uniquely situated to explore with 42 new genomes. This lineage shows the first evidence that marine adaptations are linked to natural product biosynthesis and includes at least six new species. We have identified hundreds of orphan biosynthetic gene clusters (BGCs) in these two groups and prioritized them as lead discovery targets. We have further taken this program into new directions by mining BGCs directly from environmental DNA (eDNA) using a nontargeted metagenomic approach that provides unbiased access to the biosynthetic potential of microbial diversity. These samples originate from both shallow tropical ocean sediments (1515 natural product BGCs already assembled) as well as deep sea sediments (down to 2000 meters) that are being collected for this program and have yet to be explored for natural products research. We will maximize access to these unique resources and employ innovative techniques in genome mining and synthetic biology to prioritize the targeted discovery of new antibiotic leads such as beta-lactone-containing products from eDNA that are predicted to inhibit protease virulence factors in Gram(-) bacteria. These genome mining efforts are governed by a logical workflow that prioritizes novel antibiotic discovery from poorly explored microbial resources.

项目摘要/摘要