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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：由细菌产生的复杂小分子是对抗传染病的核心。随着病原体中抗生素耐药性的不断蔓延，发现新型生物活性分子（也称为天然产物）的需求变得更加迫切。新的证据提出了这样的假设：在土壤环境中，许多天然产物可能充当细菌菌株或物种之间的信号分子。由于大多数天然产品发现工作在其设计中并未考虑到这种假设功能，因此这些分子中的绝大多数未被检测到。该提案中概述的研究旨在通过将这些分子的交流性质作为驱动因素，刺激多种土壤放线菌生产新型天然产物，从而解决这个问题。具体来说，我们提出三个目标：（1）挖掘5个新测序的链霉菌菌株的基因组中的天然产物基因，并生成报告菌株库； (2) 确定在多个高通量筛选中诱导天然产物基因表达的条件（包括 A：响应于靠近其他微生物菌株/物种的培养，B：响应于数千个天然产物文库的刺激。） ; (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型天然产物，并研究这些次级代谢产物在其自然环境中充当信号分子的假设。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以及在临床领域更好地利用天然产物提供建议。公共卫生相关性：细菌产生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，促使人们需要寻找新的、更有效的抗生素分子。新的证据提出了这样的假设：在自然环境中，这些分子（称为天然产物）实际上充当相互作用的微生物之间的信号。这里概述的研究将检验这一假设，并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型天然产物。除了寻找新颖的天然产物外，这项工作将使我们能够更加关注我们的筛选设计，从而提高我们未来天然产物发现工作的速度和效率