A sequenced-based approach for improved small molecule discovery

改进小分子发现的基于测序的方法

• 批准号: 8115914
• 负责人: PAUL R JENSEN
• 金额: $ 37.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115914
• 关键词: Actinobacteria class; Anabolism; Antibiotics; Bacteria; Base Sequence; Biological; Biological Factors; Biological Process; Biomedical Research; Carbon; Chemicals; Collection; Communities; DNA Sequence; Data; Databases; Ensure; Fermentation; Fingerprint; Gene Expression Profiling; Genetic; Genome; Genomics; Goals; Housing; Hybrids; Individual; Instruction; Internet; Lead; Light; Macrolides; Marines; Metabolism; Methodology; Methods; Modeling; Molecular; Molecular Bank; Molecular Genetics; Molecular Profiling; Orphan; Pathway interactions; Phylogenetic Analysis; Plague; Probability; Process; Production; Protocols documentation; Research; Research Project Grants; Restriction fragment length polymorphism; Sequence Analysis; Series; Source; Structure; Targeted Research; Techniques; Technology; Testing; Time Study; United States National Institutes of Health; base; comparative genomics; cytotoxicity; drug development; drug discovery; genetic profiling; genome sequencing; improved; liquid chromatography mass spectrometry; method development; microbial; microorganism; novel; public health relevance; repository; scaffold; small molecule; tool

DESCRIPTION (provided by applicant): Recent advances in DNA sequencing technologies and a better understanding of natural product biosynthesis provide newfound opportunities to improve the process by which microbial natural products are discovered. The objectives of this research are to establish a series of methodologies by which strains can be quickly assessed for natural product biosynthesis through the analysis of PCR-generated or genome sequence data. The methods will be developed using a model group of marine bacteria belonging to the genus Salinispora and then applied to a large and diverse collection of marine actinomycetes with the aim of discovering structurally diverse, new chemical entities, which will be provided to the NIH Molecular Libraries Small Molecule Repository (MLSMR). The methods include an initial, rapid molecular "fingerprinting" screen, from which the genetic potential of individual strains can be compared. Sequence-based approaches will then be applied to interpret the biosynthetic richness and novelty of strains with promising fingerprints. These methods will make it possible to predict if the metabolites produced by a strain will be new and how many different compounds in a particular structural class may be produced. Once strains with the greatest genetic potential are identified, detailed chemical studies will be performed. This approach represents a dramatic improvement over traditional paradigms in which large numbers of biosynthetically unknown strains are screened in a limited number of conditions. It will dramatically reduce the isolation of previously discovered compounds, a problem that has long plagued microbial natural product research. This approach provides a culture-independent, genome-level assessment of secondary metabolite biosynthesis as opposed to more traditional methods, which detect only those metabolites produced under a limited set of culture conditions. The methods developed will be broadly applicable to the scientific community and include the creation of a curated sequence database that can be readily downloaded and used to assess genome sequence data for pathways involved in secondary metabolite production. This research has the potential to dramatically increase the rates with which new chemical entities are discovered and made available for biomedical research. PUBLIC HEALTH RELEVANCE: The research presented in this proposal provides a method by which DNA sequence data can be used to dramatically improve the process by which natural products are discovered from microorganisms. It will generate considerable new chemical diversity that can be used for drug discovery research and to study basic biological processes. The methods developed will be made widely available to the research community and thereby have a broad impact on drug discovery and basic biomedical research.

描述（由申请人提供）：DNA测序技术的最新进展和对天然产品生物合成的更好理解为改善发现微生物天然产品的过程提供了新的机会。这项研究的目的是建立一系列方法，通过分析PCR生成或基因组序列数据，可以通过这些方法来快速评估自然产物生物合成。该方法将使用属于盐菌属的海洋细菌模型进行开发，然后应用于大量且多样化的海洋放线菌，目的是发现结构上多样的新化学实体，该实体将提供给NIH分子库小分子库（MLSMR）。这些方法包括一个初始的，快速的分子“指纹”屏幕，可以比较单个菌株的遗传潜力。然后，基于序列的方法将用于解释具有有希望的指纹的菌株的生物合成丰富度和新颖性。这些方法将有可能预测菌株产生的代谢产物是否是新的，并且可以产生特定结构类别中的多少种不同的化合物。一旦确定了具有最大遗传潜力的菌株，将进行详细的化学研究。这种方法代表了对传统范式的显着改善，在有限的条件下，对大量生物合成菌株进行了筛查。它将大大减少先前发现的化合物的隔离，这个问题长期困扰了微生物天然产品研究。这种方法提供了独立于培养的基因组水平评估次级代谢产物生物合成，而不是更传统的方法，该方法仅检测在有限的培养条件下产生的那些代谢物。开发的方法将广泛适用于科学界，并包括创建精选的序列数据库，该数据库可以很容易地下载并用于评估涉及次级代谢物生产的途径的基因组序列数据。这项研究有可能大大提高发现新化学实体并提供生物医学研究的速率。 公共卫生相关性：本提案中提出的研究提供了一种方法，可以使用DNA序列数据大幅度改善从微生物中发现天然产物的过程。它将产生相当大的新化学多样性，可用于药物发现研究并研究基本的生物学过程。开发的方法将被广泛用于研究界，从而对药物发现和基本生物医学研究产生广泛的影响。