Natural Product Genome Mining

天然产物基因组挖掘

• 批准号: 10662421
• 负责人: PAUL R JENSEN
• 金额: $ 33.79万
• 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/10662421
• 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.

项目概要/摘要 天然产物继续在医学领域提供重要的先导药物。虽然临床上大多数 抗生素来源于细菌天然产物，抗生素耐药性的出现强调 需要发现新的抗菌药物。此续订应用程序建立在高效的基础上 Jensen（微生物学/生物信息学）和 Moore（生物合成/天然 产品化学）实验室通过挖掘微生物基因组来满足这一需求 新生物活性化合物的宏基因组。我们优先考虑了两个具有化学天赋的不同群体 从世界各地海洋收集的超过 10,000 种菌株中提取用于研究的海洋细菌。我们 继续我们对专性海洋放线菌 Salinispora 的研究，它产生有效的 蛋白酶体抑制剂 salinosporamide A (Marizomib) 目前正在进行治疗脑部的 III 期试验 癌症。在这里，我们利用最近鉴定的 6 个新盐孢菌属物种和 99 个新物种 基因组来扩大我们在这个独特的分类群中的努力。我们进一步扩大基因组挖掘工作 包括 MAR4 谱系，这是我们独一无二的第二组具有化学天赋的海洋细菌 旨在探索 42 个新基因组。这个谱系显示了海洋适应的第一个证据 与天然产物生物合成相关，并包括至少六个新物种。我们已经确定 这两组中数百个孤儿生物合成基因簇（BGC），并将它们优先列为先导基因 发现目标。我们通过直接从 环境 DNA (eDNA) 使用非靶向宏基因组方法提供公正的访问 微生物多样性的生物合成潜力。这些样本来自浅热带 海洋沉积物（已组装 1515 种天然产物 BGC）以及深海沉积物（下 至 2000 米），正在为此计划收集，但尚未探索天然产品 研究。我们将最大限度地利用这些独特的资源，并采用创新技术 基因组挖掘和合成生物学优先考虑新抗生素先导化合物的发现，例如 来自 eDNA 的含有 β-内酯的产品预计可抑制蛋白酶毒力因子 革兰氏(-)细菌。这些基因组挖掘工作由优先考虑新颖的逻辑工作流程控制 从未充分探索的微生物资源中发现抗生素。