Genome mining of newly sequenced streptomycetes for novel natural products

新测序的链霉菌基因组挖掘用于新型天然产物

• 批准号: 8079102
• 负责人: Matthew F Traxler
• 金额: $ 5.13万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079102
• 关键词: Accounting; Actinobacteria class; Anabolism; Antibiotic Resistance; Antibiotics; Bacteria; Biological; Biological Assay; Biological Factors; Chemicals; Clinical; Communicable Diseases; Complex; Development; Ecology; Environment; Future; Gene Cluster; Gene Expression; Generations; Genes; Genome; Goals; Green Fluorescent Proteins; Health; Human; Immunosuppressive Agents; Industrial fungicide; Knowledge; Laboratories; Lead; Libraries; Microbe; Mining; Modeling; Modern Medicine; Nature; Organism; Physiological; Plasmids; Production; Promoter Regions; Reporter; Research; Resistance; Role; Screening procedure; Sequence Homology; Series; Signal Transduction; Signaling Molecule; Soil; Speed; Staging; Streptomyces; Structure; Testing; Therapeutic; Veterinary Medicine; Work; antimicrobial; base; chemotherapeutic agent; design; gene induction; genome sequencing; high throughput screening; human disease; improved; insight; microbial; microorganism; non-ribosomal peptide synthase; novel; pathogen; research study; response; scale up; small molecule

DESCRIPTION (provided by applicant): Complex small molecules made by bacteria are the centerpiece in the struggle against infectious disease. As antibiotic resistance among pathogens continues to spread, the need to discover novel biologically active molecules, also called natural products, grows more exigent. New evidence has led to the hypothesis that in the soil environment, many natural products may act as signaling molecules between bacterial strains or species. As most natural product discovery efforts have not accounted for this hypothetical function in their design, the overwhelming majority of these molecules have gone undetected. The research outlined in this proposal seeks to remedy this problem by incorporating the communicative nature of these molecules as a driver to stimulate production of novel natural products from several species of soil-dwelling, actinomycete bacteria. Specifically, we propose in three aims to (1) To mine the genomes of five newly sequenced streptomycete strains for natural product genes and generate a reporter strain library; (2) To identify conditions which induce natural product gene expression in multiple high-throughput screens (including A: in response to cultivation in proximity to other microbial strains/species and B: in response to stimulation by a library of thousands natural products.); and (3) Characterize and screen newly discovered natural products for antimicrobial and antitumor activity. The research proposed here is designed to simultaneously yield novel natural products of therapeutic value and investigate the hypothesis that these secondary metabolites act as signalling molecules in their natural context. Understanding the functions of these biologically active molecules in the natural environment will suggest ways to improve the efficiency of future discovery efforts and better ways to utilize natural products in the clinical arena. PUBLIC HEALTH RELEVANCE: The discovery of antibiotics made by bacteria revolutionized modern medicine. However, resistance among pathogens is on the rise, prompting a need to find new, more effective antibiotic molecules. New evidence has led to the hypothesis that in the natural environment, these molecules (called natural products) actually serve as signals between interacting microbes. The research outlined here will both test this hypothesis and utilize these interactions to stimulate the production of potentially useful novel natural products by several species of soil-dwelling bacteria. In addition to finding novel natural products, this work will allow us to bring more focus to our screening designs, thus enhancing the speed and efficiency of our future natural product discovery efforts

描述(申请人提供)：由细菌制造的复杂小分子是抗击传染病的核心。随着病原体中抗生素耐药性的持续传播，发现新的生物活性分子(也称为天然产物)的需求变得更加迫切。新的证据导致了一种假设，即在土壤环境中，许多天然产物可能在细菌菌株或物种之间充当信号分子。由于大多数天然产品的发现工作都没有在设计中考虑到这一假设功能，这些分子中的绝大多数都没有被发现。这项提案中概述的研究试图通过将这些分子的通信性质作为驱动因素来解决这一问题，以刺激几种土壤中居住的放线菌细菌生产新的天然产品。具体地说，我们提出了三个目标：(1)挖掘五个新测序的链霉菌菌株的基因组，寻找天然产物基因，并生成报告菌株文库；(2)在多个高通量筛选中识别诱导天然产物基因表达的条件(包括A：响应于接近其他微生物菌株/物种的培养，B：响应数千种天然产物的库的刺激)；以及(3)表征和筛选新发现的天然产物的抗菌和抗肿瘤活性。这里提出的研究旨在同时产生具有治疗价值的新的天然产品，并调查这些次级代谢物在其自然环境中作为信号分子的假设。了解这些生物活性分子在自然环境中的功能将为提高未来发现工作的效率和在临床领域利用天然产物提供更好的方法。与公共卫生相关：由细菌制造的抗生素的发现彻底改变了现代医学。然而，病原体之间的耐药性正在上升，这促使人们需要寻找新的、更有效的抗生素分子。新的证据导致了一种假设，即在自然环境中，这些分子(称为天然产物)实际上是相互作用的微生物之间的信号。这里概述的研究既将检验这一假设，又将利用这些相互作用来刺激几种土壤细菌产生潜在有用的新天然产品。除了寻找新的天然产品外，这项工作还将使我们能够更专注于我们的筛选设计，从而提高我们未来天然产品发现工作的速度和效率。