Natural Product Genome Mining

天然产物基因组挖掘

• 批准号: 10478234
• 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/10478234
• 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; design-build-test; 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

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.

项目总结/摘要 天然产品继续在医学上提供重要的药物线索。虽然大多数临床 抗生素是细菌的天然产物，抗生素耐药性的出现强调了 需要发现新的抗菌药物。此更新应用程序建立在高效的 詹森（微生物学/生物信息学）和摩尔（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， 新的生物活性化合物的宏基因组。我们优先考虑了两组不同的化学天赋 海洋细菌的研究从收集超过10，000菌株收集在世界各地的海洋。我们 继续我们的努力与专性海洋放线菌Salinispora，它产生强大的 蛋白酶体抑制剂salinosporamide A（Marizlavine），目前正处于治疗脑 癌在这里，我们利用最近鉴定的6个新的盐孢属物种和99个新的 基因组，以扩大我们在这一独特的分类。我们进一步扩大我们的基因组挖掘工作， 包括MAR 4谱系，这是第二组化学天赋的海洋细菌，我们是独一无二的 有42个新的基因组这一谱系首次证明了海洋生物的适应性 与天然产物生物合成有关，包括至少六个新物种。我们已经确定 在这两个群体中的数百个孤儿生物合成基因簇（BGC），并优先考虑它们作为领导 发现目标我们通过直接从BGC中挖掘BGC，进一步将该计划推向新的方向。 环境DNA（eDNA）使用非靶向宏基因组方法，提供无偏见的访问 微生物多样性的生物合成潜力。这些样本来自热带浅海 海洋沉积物（已经组装了1515个天然产物BGC）以及深海沉积物（下 至2000米），正在为该计划收集，但尚未勘探天然产品 research.我们将最大限度地利用这些独特的资源， 基因组挖掘和合成生物学，以优先发现新的抗生素线索， 来自eDNA的含β-内酯的产物，其被预测抑制蛋白酶毒力因子， 革兰氏阴性菌。这些基因组挖掘工作是由一个逻辑工作流程，优先考虑新的 抗生素的发现来自于未充分开发的微生物资源。