Universal Characterization of Natural Product Libraries

天然产物库的通用表征

• 批准号: RGPIN-2016-03962
• 负责人: Linington, Roger
• 金额: $ 4.44万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708764
• 关键词: Universal; Characterization; Natural; Product; Libraries

Organic molecules play a central role in many biological processes, from signaling molecules used by insects, to the development of the next generation of drugs for human diseases. These naturally occurring organic molecules are known as natural products'. To study these compounds effectively, scientists must be able to separate individual molecules from the complex mixtures typically found in extracts from biological samples, and identify each of these individual constituents. The main objectives of this grant are to develop new analytical chemistry tools for this identification step, and to use these new tools to explore the distributions, origins and functions of naturally occurring compounds in bacteria. Currently there are approximately 30,000 known natural products in the bacterial world, making confident identification of these compounds a daunting analytical challenge. This grant aims to address this issue in four steps. Firstly we will create a universal database of all known bacterial natural products, and analyze the similarities and differences between their structures to produce a natural products Atlas' that describes the chemical landscape occupied by these naturally occurring compounds. Secondly, we will use nuclear magnetic resonance (NMR) spectroscopy to define all the diagnostic NMR signals for molecules present in our in-house natural products library. Thirdly, we will use these NMR data in conjunction with mass spectrometric (MS) data to determine the unique set of NMR and MS features that describe each compound in the library. Finally, we will develop new computational tools that use this set of NMR and MS features to connect chemical constituents to individual compounds in the natural products Atlas, therefore defining the complete composition of every extract in the natural products library. In addition to solving this outstanding analytical chemistry challenge, our laboratory is also interested in the biochemical origin of these natural products. To address this question we will use isotopically labeled precursors to track the incorporation of precursors into natural products during bacterial cell growth. Using a unique set of labeled precursors in conjunction with the analytical platform described above we will develop a method for the systematic determination of the biochemical origin of all natural products from a given bacteria strain, and create computational tools to link these molecules to their producing genes from whole genome sequences. Finally, we will use the analytical platform to explore the chemical diversity of a new and understudied class of bacteria, from the genus Burkholderia. The goal of this work is to examine the chemical diversity produced by these organisms, and to test the hypothesis that novel microbial diversity can help us discover unique natural products with future basic science and drug development applications.

有机分子在许多生物过程中发挥着核心作用，从昆虫使用的信号分子到下一代人类疾病药物的开发。这些天然存在的有机分子被称为“天然产物”。为了有效地研究这些化合物，科学家必须能够从生物样品提取物中通常发现的复杂混合物中分离出单个分子，并识别这些单个成分中的每一种。这项资助的主要目的是为这一鉴定步骤开发新的分析化学工具，并利用这些新工具探索细菌中天然化合物的分布、起源和功能。 目前在细菌世界中大约有30，000种已知的天然产物，这使得对这些化合物的可靠鉴定成为一项艰巨的分析挑战。这项赠款旨在分四个步骤解决这一问题。首先，我们将创建一个所有已知细菌天然产物的通用数据库，并分析它们结构之间的相似性和差异，以产生一个描述这些天然化合物所占据的化学景观的天然产物图谱。其次，我们将使用核磁共振（NMR）光谱来定义我们内部天然产物库中存在的分子的所有诊断NMR信号。第三，我们将使用这些NMR数据与质谱（MS）数据相结合，以确定描述库中每种化合物的独特NMR和MS特征集。最后，我们将开发新的计算工具，使用这组NMR和MS功能将化学成分与天然产物图谱中的单个化合物联系起来，从而定义天然产物库中每个提取物的完整组成。 除了解决这一突出的分析化学挑战外，我们的实验室还对这些天然产物的生物化学来源感兴趣。为了解决这个问题，我们将使用同位素标记的前体来跟踪细菌细胞生长过程中前体掺入天然产物的情况。使用一组独特的标记前体结合上述分析平台，我们将开发一种方法，用于系统地确定来自给定细菌菌株的所有天然产物的生化来源，并创建计算工具，将这些分子与来自全基因组序列的生产基因联系起来。 最后，我们将使用分析平台来探索一种新的和未充分研究的细菌的化学多样性，来自伯克霍尔德氏菌属。这项工作的目标是研究这些生物产生的化学多样性，并测试新的微生物多样性可以帮助我们发现具有未来基础科学和药物开发应用的独特天然产物的假设。