Exploiting Microbial Diversity for Natural Product Discovery

AP 1：利用微生物多样性发现天然产物 项目总结/摘要 这项研究的主要目的是从癌症中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得到促进： 南方大学继续发展生产性微生物药物发现计划 太平洋是如此针对癌症、传染病、神经系统疾病和被忽视的热带疾病的生物测定 疾病将用于指导与这些目标相关的化合物的分离。新的结构 化合物将使用现代光谱分析解决，并产生足够的数量，以有效 临床前评价。这项研究将针对化学成分丰富的微生物类群，包括海洋微生物。 放线菌属Salinispora，探讨生物多样性与天然产物的关系 的发现这项研究得益于通过基因组测序获得的大量基因组序列数据。 联合基因组研究所社区测序计划。生物信息学分析将用于确定优先顺序 菌株进行化学评价，并建立次级代谢产物生物合成之间的关系 潜在的，分类学，以及来源于污渍的栖息地和位置。此信息将 用于开发更有效的采样策略，并提供对现存生物合成的新见解。 海洋细菌的潜力和产生结构多样性的进化过程。基因组挖掘 方法将被用来连接分子的途径，负责其生产，并促进 发现和删除复制。基于网络的工具NaPDoS（天然产物域搜索器），它简化了 将进一步开展与次级代谢物生物合成有关的基因分析，包括 其它途径类型和参考序列。新的栽培方法将被开发出来， 自然条件下，并提供生态相关的刺激，努力诱导次生代谢产物 生产这些研究将与转录组分析相结合，转录组分析将用于确定 培养条件对生物合成基因表达的影响。高灵敏度质谱分析方法 将用于更好地观察次级代谢组，并生成可用于识别 新的分子，去复制已知的化合物，并寻找地理来源之间的相关性， 生殖和次级代谢产物的产生。广泛的博士后，研究生和本科生 将在整个方案期间提供培训，包括对东道国科学家的培训。最终这 该计划旨在开发天然产品发现的改进方法，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来治疗 与美国和东道国有关的疾病。

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.