BAC Sudoku Sequencing Paradigm to Accelerate Metagenomic Natural Product Chemistr

BAC 数独测序范式加速宏基因组天然产物化学研究

• 批准号: 8712292
• 负责人: MARK R LILES
• 金额: $ 21.38万
• 依托单位: LUCIGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712292
• 关键词: American; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Artificial Chromosomes; Biodiversity; Bioinformatics; Biological Assay; Biological Factors; Businesses; Chemicals; Clinical; Cloning; Communicable Diseases; Complex; Computer Simulation; Computer software; DNA; Data; Development; Environment; Genes; Genetic; Genome; Goals; Growth; Human; Infection; Lead; Libraries; Life; Massive Parallel Sequencing; Medical; Metagenomics; Methods; Natural Products Chemistry; Nutritional; Outcomes Research; Partner in relationship; Pathway interactions; Pharmaceutical Preparations; Phase; Process; Production; Public Health; Research; Research Proposals; Resistance; Resources; Sampling; Science; Scientist; Sequence Analysis; Services; Site; Small Business Innovation Research Grant; Soil; Source; Technology; Testing; Therapeutic; Time; Universities; Work; antimicrobial; base; combinatorial; design; drug discovery; fight against; high throughput technology; improved; innovation; methicillin resistant Staphylococcus aureus; microbial; microbial community; next generation; next generation sequencing; novel; pathogen; public health relevance; screening; small molecule; small molecule libraries; tool

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.

描述（由申请人提供）：在我们对针对微生物病原体的防御措施中，社会需要新化合物，其中许多对现有治疗剂具有抗药性。具有潜在新型作用机制的新抗菌化合物的最佳来源是在自然环境中，尤其是土壤，这些土壤具有微生物寿命最大的多样性。这项研究建议推进了宏基因组学的科学，即从整个微生物群落的DNA克隆，以发现新型抗生素并确定临床开发的最佳铅候选者。露西根公司（Lucigen Corporation）和奥本大学（Auburn University）的科学家结合了关键的技术突破，从而改善了用于筛选小分子的宏基因组库的范式。在此过程中，主要限制步骤是以生物活性筛选自然产品库所需的数百万生物测定。该阶段I SBIR将开发新的工具，用于大规模平行的下一代测序和分析宏基因组库，以发现硅中的天然产物途径。该过程将加速自然产品化学发现五十倍，同时消除生物测定的偏见。这项研究的成功结果还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能力。

项目成果

Discovery of Novel Biosynthetic Gene Cluster Diversity From a Soil Metagenomic Library.

• DOI: 10.3389/fmicb.2020.585398
• 发表时间: 2020
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Santana-Pereira ALR;Sandoval-Powers M;Monsma S;Zhou J;Santos SR;Mead DA;Liles MR
• 通讯作者: Liles MR