BAC Sudoku Sequencing Paradigm to Accelerate Metagenomic Natural Product Chemistr

描述(申请人提供)：在我们防御微生物病原体的武器库中，社会上需要新的化合物，其中许多对现有的治疗方法越来越有抵抗力。具有潜在新作用机制的新抗菌化合物的最佳可能来源是在自然环境中，特别是拥有最多微生物生命多样性的土壤中。这项研究提案推进了元基因组学，即从整个微生物群落中克隆DNA，以发现新的抗生素并确定临床开发的最佳候选药物。Lucigen公司和奥本大学的科学家们将关键技术突破结合在一起，形成了筛选小分子元基因组文库的改进范式。在这一过程中，一个主要的速度限制步骤是筛选具有生物活性的小分子天然产物库所需的数百万次生物检测。这个第一阶段的SBIR将开发新的工具，用于大规模并行的下一代元基因组文库的测序和分析，以发现硅胶中的天然产物途径。这一过程将使天然产物的化学发现速度提高50倍，同时消除生物分析的偏见。这项研究的成功结果还将彻底改变对人类具有重大营养和医学价值的复杂基因组的分析能力。

DESCRIPTION (provided by applicant): There is societal need for new compounds in our arsenal of defenses against microbial pathogens, many of which are increasingly resistant to existing therapeutics. The best possible source for new antimicrobial compounds with potentially novel mechanisms of action is within natural environments, particularly soils, which have the greatest diversity of microbial life. This research proposal advances the science of metagenomics, the cloning of DNA from entire microbial communities, to discover novel antibiotics and identify the best lead candidates for clinical development. Scientists at Lucigen Corporation and Auburn University have combined key technological breakthroughs that result in an improved paradigm for screening metagenomic libraries for small molecules. A major rate limiting step in this process is the millions of bioassays required to screen natural product libraries for small molecules with bioactivity. This Phase I SBIR will develop new tools for massively parallel next-generation sequencing and analysis of the metagenomic libraries to discover natural product pathways in silico. The process will accelerate natural product chemistry discovery fifty-fold while eliminating the bias of biological assays. The successful outcome of this research will also revolutionize the ability to completely analyze complex genomes of significant nutritional and medical value to humans.