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.

项目摘要/摘要 天然产物继续在医药领域提供重要的药物先导。而大多数临床上的 抗生素来源于细菌天然产物，抗生素耐药性的出现强调 发现新的抗菌药线索的必要性。此续订应用程序构建在高效的 Jensen(微生物学/生物信息学)和Moore(生物合成/天然)之间的合作 产品化学)实验室通过挖掘微生物基因组和 新生物活性化合物的元基因组。我们已经优先考虑了两组不同的化学天赋 从全球海洋收集的10,000株细菌中进行研究的海洋细菌。我们 继续我们对专性海洋放线菌Salinispora的努力，它产生有效的 蛋白酶体抑制剂Salinosporamide A(Marizomib)目前处于治疗大脑的第三阶段试验 癌症。在这里，我们利用最近发现的六个新种和99个新种 基因组，以扩大我们在这个独特的分类群中的努力。我们进一步扩大了我们的基因组挖掘努力 包括MAR4谱系，这是海洋细菌的第二个具有化学天赋的群体，我们对它是独一无二的 位于探索42个新基因组的位置。这一血统首次证明了海洋适应 与天然产物生物合成有关，并包括至少六个新物种。我们已经确定了 这两组中有数百个孤儿生物合成基因簇(BGC)，并将它们列为优先考虑的铅 发现目标。我们通过直接从BGC中挖掘BGC，进一步将该程序带入了新的方向 环境DNA(EDNA)使用非目标元基因组学方法，提供无偏见的访问 微生物多样性的生物合成潜力。这些样品来自浅海热带地区 海洋沉积物(已组装的1515个天然产物BGC)以及深海沉积物(向下 至2000米)，正在为该计划收集，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，并在 基因组挖掘和合成生物学，优先发现新的抗生素线索，如 来自EDNA的含有β-内酯的产品被预测为抑制蛋白酶毒力因子 革兰(-)细菌。这些基因组挖掘工作是由一个逻辑工作流程管理的，该工作流程优先考虑 从开发不足的微生物资源中发现抗生素。