BAC Sudoku Sequencing Paradigm to Accelerate Metagenomic Natural Product Chemistr

描述（由申请人提供）：社会需要新的化合物来防御微生物病原体，其中许多对现有疗法的耐药性越来越强。具有潜在新型作用机制的新型抗菌化合物的最佳可能来源是自然环境，特别是微生物生命多样性最大的土壤。这项研究提案推进了宏基因组学的科学，即从整个微生物群落中克隆DNA，以发现新型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结合了关键的技术突破，从而改进了筛选小分子宏基因组文库的范例。该过程中的主要限速步骤是筛选具有生物活性的小分子的天然产物库所需的数百万次生物测定。该阶段I SBIR将开发用于宏基因组文库的大规模并行下一代测序和分析的新工具，以通过计算机发现天然产物途径。该过程将使天然产物化学发现加速50倍，同时消除生物测定的偏差。这项研究的成功结果也将彻底改变对人类具有重要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.