Exploiting Microbial Diversity for Natural Product Discovery

利用微生物多样性来发现天然产品

• 批准号: 9334337
• 负责人: PAUL R JENSEN
• 金额: $ 16.56万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9334337
• 关键词: Actinomyces Infections; Address; Algae; Anabolism; Antibiotics; Artemia; Bacteria; Bacterial Genome; Biodiversity; Bioinformatics; Biological; Biological Assay; Biological Testing; Chemicals; Classification; Collaborations; Collection; Communicable Diseases; Communities; Complex; Country; Coupled; Custom; Data; Development; Disease; Evaluation; Fermentation; Fiji; Foundations; Funding; Gene Expression; Generations; Genes; Genome; Genomics; Geographic Locations; Geography; Habitats; Institutes; Ions; Joints; Lead; Libraries; Link; Location; Malignant Neoplasms; Marines; Mass Spectrum Analysis; Metabolism; Methods; Microbiology; Mining; Modernization; Molecular; Natural Products; Natural Products Chemistry; Nutrient; Orphan; Pathway interactions; Phylogenetic Analysis; Phylogeny; Physiologic pulse; Porifera; Postdoctoral Fellow; Process; Production; Research; Resources; Running; Sampling; Scientist; Sequence Analysis; Solomon Islands; Staining method; Stains; Stimulus; Structure; Surface; System; Taxonomy; Techniques; Technology Transfer; Training; Transcription Factor AP-1; Transcription Factor AP-2 Alpha; Trees; Universities; Visual; ascidian; base; design; drug candidate; drug discovery; genomic RNA; graduate student; improved; insight; metabolome; microbial; microbial community; microorganism; neglected tropical diseases; nervous system disorder; novel; novel strategies; novel therapeutics; pre-clinical; programs; rapid technique; research clinical testing; scale up; screening; small molecule; tool; transcriptome; transcriptome sequencing; transcriptomics; undergraduate student; web site; web-based tool

AP1: Exploiting Microbial Diversity for Natural Product Discovery Project Summary/Abstract The primary objective of the proposed research is to discover new, small molecule drug candidates from marine microorganisms cultured from Fiji and the Solomon Islands. This objective will be facilitated through the continued development of a productive microbial drug discovery program at the University of the South Pacific. Bioassays targeting cancer, infectious disease, neurological disorders, and neglected tropical diseases will be used to guide the isolation of compounds relevant to these targets. The structures of new compounds will be solved using modern spectral analyses and produced in sufficient quantities for effective pre-clinical evaluation. The research will target chemically rich microbial taxa including the marine actinomycete genus Salinispora and explore the relationships between biotic diversity and natural product discovery. The research benefits from a wealth of genome sequence data that has been acquired through the Joint Genome Institutes Community Sequencing Program. Bioinformatic analyses will be used to prioritize strains for chemical evaluation and to establish relationships between secondary metabolite biosynthetic potential, taxonomy, and the habitats and locations from which the stains originate. This information will be used to develop more effective sampling strategies and to provide new insight into the extant biosynthetic potential of marine bacteria and the evolutionary processes that generate structural diversity. Genome mining approaches will be used to link molecules to the pathways responsible for their production and to facilitate discovery and de-replication. The web-based tool NaPDoS (Natural Product Domain Seeker), which simplifies the analysis of genes involved with secondary metabolite biosynthesis, will be further developed to include additional pathway types and reference sequences. New cultivation methods will be developed that mimic natural conditions and provide ecologically relevant stimuli in an effort to induce secondary metabolite production. These studies will be coupled with transcriptome analyses, which will be used to determine the effects of culture conditions on biosynthetic gene expression. Highly sensitive methods in mass spectrometry will be used to better visual the secondary metabolome and generate networks that can be used to recognize new molecules, de-replicate known compounds, and search for correlations between geographic origin, phylogeny, and secondary metabolite production. Extensive post-doctoral, graduate, and undergraduate training will be provided throughout the program including training for host country scientists. Ultimately, this program aims to develop improved methods for natural product discovery and apply these approaches to the microbial resources in Fiji and the Solomon Islands in an effort to discover new drug candidates to treat diseases relevant to the US and the host nations.

AP1：开发微生物多样性以发现天然产品 项目摘要/摘要 这项研究的主要目标是发现新的小分子候选药物 从斐济和所罗门群岛培养的海洋微生物。这一目标将通过以下方式促进实现 在南方大学继续开展生产性微生物药物发现计划 太平洋。针对癌症、传染病、神经疾病和被忽视的热带地区的生物检测 将使用疾病来指导与这些目标相关的化合物的分离。《新闻》的结构 化合物将使用现代光谱分析进行分解，并生产足够数量的有效化合物 临床前评估。这项研究将针对化学成分丰富的微生物分类群，包括海洋 放线菌属盐生孢属及其生物多样性与天然产物的关系 发现号。这项研究得益于通过 联合基因组研究所社区测序计划。将使用生物信息学分析来确定优先顺序 用于化学评价的菌株和建立次生代谢物生物合成之间的关系 潜在的，分类，以及污渍起源的栖息地和位置。这一信息将是 用于开发更有效的采样策略，并为现有的生物合成提供新的见解 海洋细菌的潜力以及产生结构多样性的进化过程。基因组挖掘 将使用方法将分子连接到负责它们产生的途径，并促进 发现和重复数据删除。基于Web的工具NaPDoS(自然产品领域搜索者)，它简化了 对次生代谢物生物合成相关基因的分析将进一步发展到包括 其他途径类型和参考序列。将开发模仿的新的栽培方法 并提供与生态相关的刺激，以努力诱导次生代谢物 制作。这些研究将与转录组分析相结合，这将被用来确定 培养条件对生物合成基因表达的影响。高灵敏的质谱学方法 将被用来更好地观察次生代谢组并产生可用于识别的网络 新的分子，去复制已知的化合物，并寻找地理来源之间的关联， 系统发育和次生代谢物的产生。广泛的博士后、研究生和本科生 培训将贯穿整个方案，包括对东道国科学家的培训。归根结底，这 该计划旨在开发改进的天然产品发现方法，并将这些方法应用于 斐济和所罗门群岛的微生物资源，以努力发现新的候选药物进行治疗 与美国和东道国相关的疾病。