New Methodologies for Accelerating Natural Product Discovery

加速天然产品发现的新方法

• 批准号: 7845955
• 负责人: BRIAN O BACHMANN
• 金额: $ 37.13万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845955
• 关键词: Actinobacteria class; Address; Adopted; Area; Biodiversity; Biological; Biological Factors; Biological Preservation; Charge; Chemicals; Complement; Complex; Computing Methodologies; Crude Extracts; Data; Development; Dimensions; Ecosystem; Emerging Technologies; Enzymes; Gases; Genomics; Goals; In Situ; Ions; Maps; Mass Spectrum Analysis; Measures; Metabolic; Methodology; Methods; Minor; Molecular; Molecular Bank; Molecular Conformation; Molecular Structure; Myxococcales; Natural Products Chemistry; Organism; Peptides; Pharmaceutical Preparations; Phase; Process; Production; Property; PubChem; Request for Applications; Research Personnel; Savings; Screening procedure; Source; Structure; Techniques; Time; United States National Institutes of Health; Universities; analytical method; base; cryogenics; innovation; interest; ion mobility; microorganism; programs; public health relevance; receptor; repository; response; small molecule; small molecule libraries; tool; two-dimensional

DESCRIPTION (provided by applicant): This application is in response to a Request for Applications for New Methodologies in Natural Product Chemistry (RFA-RM-09-005). We propose a campaign to establish a new program of natural product discovery based on a) a new biological source in the form of cave derived microorganisms and b) a new analytical method based on ion mobility mass spectrometry (IM-MS). These two aspects will open up a new reservoir of biodiversity for the discovery of natural products and provide a new method to accelerate the discovery of compounds in crude extracts and reduce the labor involved in their isolation. The labor and time savings derive from the ability to prioritize metabolites for isolation and structure elucidation based on their IM-MS measured properties. Aim 1. Develop natural product analysis using ion mobility mass spectroscopy (IM-MS). IM-MS is a form of 2-dimensional mass spectrometry that plots both mass/charge ratio and gas-phase collision cross- sectional area, which may be directly related to molecular conformation and functionality. We will evaluate the correlation of mass-collision area ratio to natural product class and compare these correlations to computationally predicted values. These data will map compound structure, class and conformation to IM-MS values. Aim 2. Develop cave microorganisms as a new source of natural product diversity. The isolation, cryogenic preservation and genotaxonomic characterization of culturable hypogean myxobacteria and actinobacteria will provide a new reservoir for natural product discovery and a source of extract material for the subsequent aims. Aim 3. Develop IM-MS as a method to identify candidates in extracts. A subset of taxonomically unique organisms will be evaluated for secondary metabolic potential by IM-MS. Compounds with IM-MS properties that distinguish compound class, functionality or unique conformation will be targeted for isolation/structure elucidation. The aims are parallel, but synergistic. New methods for identifying secondary metabolites from complex sources are essential for accelerating discovery. New sources of biodiversity are continuously needed to expand access to their biosynthetic molecular diversity. Cave microorganisms will provide a biological source of extracts needed to develop IM-MS as tool for identification of secondary metabolites in extracts. The natural products discovered by proposed methodologies will be available to the NIH Molecular Libraries Program (MLP) including Molecular Libraries Probe Production Centers Network (MLPCN), Molecular Libraries Small- Molecule Repository (MLSMR) and PubChem. PUBLIC HEALTH RELEVANCE: Natural products are an excellent source for drugs, but they are difficult to discover as they must be identified as minor components of complex extracts from biological sources. We propose to develop two-dimensional separations on the basis of molecular structure and mass to guide the identification of natural products from complex biological sources. Furthermore, cave derived microorganisms, a previously untapped source of biodiversity, will be investigated for natural product discovery.

描述（由申请人提供）：此申请是响应自然产品化学中新方法的申请的请求（RFA-RM-09-005）。我们提出了一项运动，以基于a）洞穴衍生微生物的形式建立一个新的自然产品发现计划，b）基于离子移动性质谱（IM-MS）的新分析方法。这两个方面将为发现天然产品的新生物多样性储备开放，并提供了一种新方法，以加速原油中的化合物并减少隔离所涉及的劳动力。劳动和时间节省源于基于IM-MS测得的特性来确定代谢物进行隔离和结构阐明的能力。 AIM 1。使用离子迁移率质谱（IM-MS）进行天然产品分析。 IM-MS是二维质谱法的一种形式，该形式绘制了质量/电荷比和气相碰撞横截面区域，这可能与分子构象和功能直接相关。我们将评估质量面积比与自然产品类别的相关性，并将这些相关性与计算预测值进行比较。这些数据将将复合结构，类和构图映射到IM-MS值。 目标2。发展洞穴微生物作为自然产品多样性的新来源。可培养的低菌病和静脉细菌的隔离，低温保存和基因性表征将为自然产品发现提供新的储层，并为后续目标提供提取物材料的来源。 目标3。开发IM-MS作为识别提取物中候选者的方法。 IM-MS将评估一部分具有分类学独特的生物的二级代谢潜力。具有区分化合物类，功能或唯一构象的IM-MS特性的化合物将用于隔离/结构阐明。 目的是平行的，但协同作用。从复杂来源识别二级代谢产物的新方法对于加速发现至关重要。不断需要新的生物多样性来源来扩展对其生物合成分子多样性的访问。洞穴微生物将提供开发IM-MS作为鉴定提取物中二级代谢物的工具所需提取物的生物学来源。 NIH分子图书馆计划（MLP）可供选择，包括分子文库探针生产中心网络（MLPCN），分子库小分子存储库（MLSMR）和Pubchem。 公共卫生相关性：天然产品是药物的绝佳来源，但是很难发现它们，因为它们必须被确定为来自生物来源的复杂提取物的次要组成部分。我们建议根据分子结构和质量开发二维分离，以指导从复杂的生物学来源鉴定天然产物。此外，将研究自然产品发现的洞穴衍生微生物，这是先前未开发的生物多样性来源。