Natural Product Genome Mining

天然产物基因组挖掘

• 批准号: 10727679
• 负责人: PAUL R JENSEN
• 金额: $ 8.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10727679
• 关键词: Acceleration; Actinobacteria class; Address; Anabolism; Antibiotics; Aquaculture; 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; Gifts; 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; Productivity; Proteasome Inhibitor; Research; Resources; Sampling; Science; Signaling Molecule; Synthetic Genes; Taxon; Techniques; Testing; Time; Vanadium; Virulence; Virulence Factors; antimicrobial; chemical group; comparative genomics; deep ocean; design; design,build,test; drug discovery; emerging antibiotic resistance; experimental study; gene synthesis; halogenation; human disease; innovation; insight; isoprenoid; marine; 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

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

项目成果

Function-related replacement of bacterial siderophore pathways.

与功能相关的替代细菌辅助途径。

• DOI: 10.1038/ismej.2017.137
• 发表时间: 2018-03
• 期刊: The ISME journal
• 作者: Bruns H;Crüsemann M;Letzel AC;Alanjary M;McInerney JO;Jensen PR;Schulz S;Moore BS;Ziemert N
• 通讯作者: Ziemert N

Microbe Profile: Salinispora tropica: natural products and the evolution of a unique marine bacterium.

微生物概况：热带盐孢菌：天然产物和独特海洋细菌的进化。

• DOI: 10.1099/mic.0.001163
• 发表时间: 2022
• 期刊: Microbiology (Reading, England)
• 作者: Jensen,PaulR

Ecological implications of hypoxia-triggered shifts in secondary metabolism.

缺氧引发的次生代谢变化的生态学意义。

• DOI: 10.1111/1462-2920.13700
• 发表时间: 2017
• 期刊: Environmental microbiology
• 影响因子: 5.1
• 作者: Gallagher,KelleyA;Wanger,Greg;Henderson,Jane;Llorente,Mark;Hughes,ChambersC;Jensen,PaulR
• 通讯作者: Jensen,PaulR

Vertical Inheritance Facilitates Interspecies Diversification in Biosynthetic Gene Clusters and Specialized Metabolites.

• DOI: 10.1128/mbio.02700-21
• 发表时间: 2021-12-21
• 期刊: mBio
• 影响因子: 6.4
• 作者: Chase AB;Sweeney D;Muskat MN;Guillén-Matus DG;Jensen PR
• 通讯作者: Jensen PR

Identification of Thiotetronic Acid Antibiotic Biosynthetic Pathways by Target-directed Genome Mining.

• DOI: 10.1021/acschembio.5b00658
• 发表时间: 2015-12-18
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Tang X;Li J;Millán-Aguiñaga N;Zhang JJ;O'Neill EC;Ugalde JA;Jensen PR;Mantovani SM;Moore BS
• 通讯作者: Moore BS