Genomics Accelerated Natural Product Discovery

基因组学加速天然产物发现

• 批准号: 10683937
• 负责人: Douglas Alan Mitchell
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683937
• 关键词: Acceleration; Algorithms; Amphotericin; Anabolism; Animals; Antifungal Agents; Ants; Bacteria; Bacterial Genome; Big Data; Binding; Biochemical; Biochemistry; Bioinformatics; Biological; Biological Assay; Biology; Catalogs; Cells; Chemicals; Chemistry; Cholesterol; Classification; Communities; Data; Databases; Deposition; Development; Drug Kinetics; Educational process of instructing; Emerging Technologies; Enzymes; Ergosterol; Exhibits; Explosion; Family; Future; Genbank; Gene Cluster; Gene Structure; Genetic; Genome; Genomics; Geography; Human; Iceberg; Insecta; Invertebrates; Knowledge; Length; Life; Macrolides; Malignant Neoplasms; Membrane; Metabolic; Metagenomics; Methods; Microbe; Mining; Modernization; Molecular; Molecular Probes; Molecular Structure; Mus; Natural Products; Natural Products Chemistry; Natural Source; Nematoda; Open Reading Frames; Pathway interactions; Peptides; Pharmaceutical Preparations; Planet Earth; Polyenes; Process; Research Personnel; Resources; Ribosomes; S-Adenosylhomocysteine; S-Adenosylmethionine; Shapes; Soil; Source; Specificity; Sterols; Streptomyces; Structure; Taxonomy; Toxic effect; bioinformatics tool; crosslink; fungus; genome sequencing; genomic data; human disease; improved; in vivo; innovation; interest; member; metagenome; microbial; microbiome; microbiome sequencing; novel; peptide natural products; polyketides; scaffold; screening; symbiont; synthetic biology; tool; user-friendly; virtual

Our group is broadly interested in the chemical biology of natural products (NPs). We seek to identify new mo- lecular structures that are formed by unusual enzymatic transformations. One successful approach was the de- velopment of an innovative discovery workflow that embraces big data genomics. With the sequencing revolution picking up pace, we are leveraging this vast resource to bioinformatically identify, classify, and experimentally characterize carefully selected novel NPs. For this project, we focus on bacterial NPs for several reasons: (i) Bacteria are the most historically significant source of molecular probes and drug leads. Such compounds re- vealed fundamentally new biology and also transformed the treatment of many human diseases. (ii) Bacteria dominate all other forms of life in terms of genetic/taxonomic breadth, chemical/metabolic capabilities, and geo- graphic/environmental diversity. (iii) Bacteria tend to organize the genes involved in NP biosynthesis into neatly organized clusters, which facilitates their bioinformatic identification and subsequent experimental characteriza- tion. This proposal unites big data genomics, synthetic biology, and modern chemical biology to structurally and functionally characterize novel NPs. Herein we target pathways predicted to showcase the molecular results of new enzymatic transformations with a strong focus on metagenome-derived pathways, especially from bacteria that associate with invertebrate animals. Several readily cultivated bacterial genera have been extensively studied, which established certain taxa as prolific sources of NPs (e.g. soil-dwelling Streptomyces). However, knowledge is sparse on less cultivable bac- teria, which represent the overwhelming majority of microbial diversity. Only relatively recently have the requisite technologies emerged to sequence and assemble metagenomic data into reads of useful length. As part of this project, we have repurposed RODEO, our open access, user-friendly genome-mining tool to analyze data deriv- ing from metagenome/microbiome sequencing projects. “MetaRODEO” will be validated through isolation and characterization of several distinct NP classes. We center our efforts on NPs from symbiotic bacteria of inverte- brates, given that numerous species have longstanding and intimate partnerships with their lower animal hosts. Evolutionary forces have undoubtedly shaped the bioactivity, improved the pharmacokinetics, and reduced the animal toxicity of NPs from bacterial symbionts compared to soil-dwelling counterparts. This project involves three interconnected but independently achievable specific aims. Aim I focuses on genomic sequencing, bioinformatics analysis, and isolation/characterization of first-in-class RiPPs from the invertebrate microbiome. Aim II centers on new RiPPs and other NPs derived from microbiome-derived biosynthetic path- ways that employ radical SAM enzymes. Aim III expands the environmental origin and chemistry of NPs identi- fied by our algorithm by targeting polyene macrolides. Each aim will elucidate new NP structures and evaluate biological activity using a rigorous, multi-tiered strategy.

我们的小组对天然产品（NP）的化学生物学广泛感兴趣。我们试图确定新的mo- 由异常酶促转化形成的腹膜结构。一种成功的方法是 具有大数据基因组学的创新发现工作流程的速度。随着测序革命 拾起空间，我们正在利用这种庞大的资源来生物信息上识别，对实验进行分类和分类 表征精心选择的新型NP。对于这个项目，我们以多种原因专注于细菌NP：（i） 细菌是分子探针和药物铅的历史最重要的来源。这样的化合物重新 从根本上讲是新的生物学，也改变了许多人类疾病的治疗。 （ii）细菌 以遗传/分类广度，化学/代谢能力和地理位置来统治所有其他形式的生活形式 图形/环境多样性。 （iii）细菌倾向于将涉及NP生物合成的基因整齐地组织 有组织的群集，其具有生物信息学鉴定以及随后的实验特征 tion。该建议将大数据基因组学，合成生物学和现代化学生物学团结起来，在结构和 功能表征新颖的NP。在此，我们针对预测的途径展示了 新的酶转化，重点是元基因组来源的途径，尤其是细菌 与无脊椎动物相关。 几个容易培养的细菌属已广泛研究，该属确定了某些分类单元为 NP的多产来源（例如土壤居链霉菌）。但是，知识在较少栽培的BAC上很少 Teria，代表了绝大多数微生物多样性。只有最近才有必要的 技术出现以序列并将宏基因组数据组装成有用长度的读取。作为其中的一部分 项目，我们有重新利用的牛仔竞技表 来自元基因组/微生物组测序项目。 “ metarodeo”将通过隔离和 表征几个不同的NP类。我们将努力集中在非佛经者共生细菌的NP上 鉴于许多物种与其下动物宿主建立了长期和亲密的伙伴关系。 进化力无疑塑造了生物活性，改善了药代动力学并降低了生物活性。 与土壤居民相比，来自细菌符号的NP的动物毒性。 该项目涉及三个相互联系但独立实现的特定目标。目的我专注于基因组 从无脊椎动物的第一类ripp的测序，生物信息学分析和隔离/表征 微生物组。 AIM II以新的RIPP和其他NP为中心，这些NP来自微生物组衍生的生物合成途径 - 采用激进SAM酶的方式。 AIM III扩展了NPS识别的环境起源和化学 通过靶向多烯大环内酯类药物，由我们的算法融合。每个目标都将阐明新的NP结构并评估 使用严格的多层策略的生物活性。