Natural Product Genome Mining

天然产物基因组挖掘

• 批准号: 8111908
• 负责人: PAUL R JENSEN
• 金额: $ 30.43万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111908
• 关键词: Actinobacteria class; Affinity; Anabolism; Antibiotics; Antineoplastic Agents; Bacteria; Bahamas; Bioinformatics; Biological; Biological Factors; Biological Testing; Biology; Biomedical Research; Cell physiology; Chemicals; Chemistry; Clinic; Clinical Treatment; Clinical Trials; Collaborations; Collection; Fermentation; Fiji; Gene Cluster; Genes; Genome; Genomics; Goals; Health; Institutes; Laboratories; Location; Macrolides; Malignant Neoplasms; Marines; Medicine; Metabolic; Methods; Microbial Genome Sequencing; Mining; Molecular; Monitor; Mutagenesis; Natural Product Drug; Natural Products Chemistry; Orphan; Output; Palau; Pharmaceutical Preparations; Probability; Process; Production; Property; Prophages; Proteins; Public Health; Research; Resources; Role; Sequence Analysis; Siderophores; Site; Source; Structure; Taxon; Techniques; Time; Transcript; antineoplastic antibiotics; bacterial genetics; base; clinically relevant; comparative genomics; drug candidate; drug discovery; genetic manipulation; genome sequencing; innovation; microbial; novel; programs; public health relevance; salinosporamide A; scaffold; tRNA Ligase; tool; yersiniabactin

DESCRIPTION (provided by applicant): Marine actinomycetes belonging to the genus Salinispora have proven to be a rich source of novel secondary metabolites including one compound (salinosporamide A) that is currently in clinical trials for the treatment of cancer. Despite extensive fermentation studies of S. tropica and S. arenicola, recent genome sequencing has revealed an abundance of novel biosynthetic gene clusters in both taxa whose products have yet to be discovered. This new information provides clear evidence that even these well-studied environmental bacteria continue to represent an important resource for natural product discovery. We have amassed a large collection of several thousand Salinispora isolates from numerous worldwide collection sites that produce distinct suites of secondary metabolites indicating that the overall breadth of biosynthetic diversity within the genus is far greater than previously recognized. We are now presented with a unique opportunity to combine the powerful techniques of genome sequence analysis, along with the ability to genetically manipulate Salinispora in the laboratory, to integrate bacterial genetics into the natural product drug discovery process. We therefore propose a comprehensive and multi-disciplinary program in which innovative genome mining techniques will be employed to effectively enhance the discovery of natural products from this new group of marine bacteria. To accomplish the broad goals outlined in this application, the Moore and Jensen laboratories have established a long-term collaboration that seamlessly integrates the complementary expertise of both research programs. We propose two major aims. First, we will isolate, characterize, and test for biological activity new natural products from S. tropica strain CNB-440 and S. arenicola CNS-205 discovered through bioinformatics-based, genome mining techniques. From our comprehensive genome sequencing and annotation of both strains, we have identified five orphan gene sets to explore that have a high probability to yield novel metabolites with promising biological properties and novel enzymatic mechanisms in natural product biosynthesis. Second, we will sequence and annotate draft genomes of four new Salinispora strains, including two phylotypes of the new species S. pacifica and two geographically and metabolically distinct S. arenicola strains, and mine them for the production of novel secondary metabolites. PUBLIC HEALTH RELEVANCE: Natural microbial products occupy a central role in medicine by providing the majority of the antibiotics and anticancer agents employed in the clinic as well as important biomedical research tools used to discover and probe cellular processes. As the discovery rate of new chemical entities from bacteria diminishes over time, innovative methods are urgently needed to provide new molecular scaffolds from which drug leads can be developed. By combining a new marine bacterial resource that has a proven track record in providing clinically relevant drug candidates together with a comprehensive natural product discovery approach that employs innovative analyses of microbial genome sequences and state of the art genetic manipulation, we aim to unlock the biosynthetic potential of a select group of bacteria and provide new compounds for biological testing. These molecules have the potential to be developed into new anticancer agents or antibiotics, or provide the structural motifs from which such drugs can be developed. Public health may directly benefit from these discoveries or, in the long term, from advances in the efficiency of the natural product discovery process that will be gained from this research.

描述（由申请人提供）：已证明属于Salinispora属的海洋放线菌是新型次级代谢物的丰富来源，包括一种目前正在临床试验中用于治疗癌症的化合物（Salinosporamide A）。尽管对S. tropica和S. arenicola，最近的基因组测序揭示了丰富的新的生物合成基因簇在这两个类群的产品尚未被发现。这些新的信息提供了明确的证据，即使是这些经过充分研究的环境细菌仍然是天然产品发现的重要资源。我们已经积累了一个大的收集数千Salinispora分离物从世界各地的许多收集网站，产生不同的套房的次生代谢产物，表明该属内的生物合成多样性的整体广度远远大于以前认识到的。我们现在有一个独特的机会，联合收割机结合强大的基因组序列分析技术，沿着的能力，在实验室遗传操纵盐孢菌，整合细菌遗传学到天然产物药物发现过程。因此，我们提出了一个全面的和多学科的计划，其中创新的基因组挖掘技术将被用来有效地提高从这个新的海洋细菌群的天然产物的发现。为了实现本申请中概述的广泛目标，摩尔和詹森实验室建立了长期合作关系，无缝集成了两个研究项目的互补专业知识。我们提出两个主要目标。首先，我们将分离、鉴定和测试新的天然产物的生物活性。tropica菌株CNB-440和S. arenicola CNS-205通过基于生物信息学的基因组挖掘技术发现。从我们对这两种菌株的全面基因组测序和注释中，我们已经确定了五个孤儿基因集，以探索这些基因集很有可能产生具有有前途的生物学特性和天然产物生物合成中的新酶机制的新代谢产物。其次，我们将测序和注释四个新的盐孢属菌株的基因组草案，包括两个新物种S。pacifica和两种地理位置和代谢不同的S. arenicola菌株，并挖掘它们用于生产新的次级代谢产物。公共卫生相关性：天然微生物产品在医学中占据核心地位，提供了临床上使用的大多数抗生素和抗癌剂，以及用于发现和探测细胞过程的重要生物医学研究工具。随着从细菌中发现新化学实体的速度随着时间的推移而降低，迫切需要创新方法来提供新的分子支架，从而可以开发药物先导物。通过结合一种新的海洋细菌资源，该资源在提供临床相关候选药物方面具有良好的记录，以及采用微生物基因组序列创新分析和最先进遗传操作的综合天然产物发现方法，我们的目标是解锁一组选定细菌的生物合成潜力，并为生物测试提供新的化合物。这些分子有可能被开发成新的抗癌剂或抗生素，或提供可以开发此类药物的结构基序。公共卫生可能直接受益于这些发现，或者从长远来看，受益于这项研究将获得的天然产品发现过程效率的提高。