Mapping and Understanding Production of Natural Products in Fungi

绘制和了解真菌天然产物的生产

• 批准号: 10522724
• 负责人: NEIL L KELLEHER
• 金额: $ 54.29万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522724
• 关键词: Accounting; Actinobacteria class; Address; Agrochemicals; Antibiotics; Antifungal Agents; Antineoplastic Agents; Antiparasitic Agents; Ascomycota; Aspergillus nidulans; Bacteria; Bioinformatics; Biological; Caspofungin; Cells; Chemicals; Chromosomes; Clinical; Cloning; Collaborations; Collection; Cyclosporins; Data; Data Set; Euchromatin; Funding; Fungal Genome; Future; Gene Cluster; Generations; Genes; Genetic; Genome; Genomic approach; Genomics; Genotype; Goals; Histones; Hot Spot; Immune; Improve Access; Inflammatory Response; Link; Lovastatin; Mass Spectrum Analysis; Medicine; Metabolism; Methodology; Methods; Modeling; Molecular Biology; Natural Products; Output; Pathway interactions; Penicillins; Phenotype; Production; Proteins; Public Health; Reader; Recording of previous events; Reporter; Research; Secure; Soil; Source; Sterigmatocystin; Structure; Surveys; Technology; Tertiary Protein Structure; Testing; Therapeutic; Time; Work; Zebrafish; base; bioactive natural products; economic value; fungus; genome sequencing; genomic locus; immunoregulation; improved; insight; member; metabolomics; migration; neutrophil; new technology; novel; overexpression; response; screening; screening program; success; tool

Project Summary/Abstract The goal of this project is to improve a genome-driven, correlation-based platform to unearth and produce new bioactive compounds from fungi. This platform and research will deliver access to a large repertoire of fungal natural products (NPs), which historically have been a great source of new medicines and useful compounds. Typical estimates have NPs and their derivatives accounting for ca. 75% of currently used antibiotics and nearly 60% of anti-cancer drugs along with numerous antiviral, antiparasitic, antifungal, and immunosuppressive medicines. Despite their historical successes, traditional screening programs have been severely curtailed due to declining numbers of promising new candidates and lack of ready access to new compounds. At the same time, analysis of over one thousand fungal genomes suggests that tens of thousands of high-value NPs have yet to be identified and screened. Thus, new technologies are needed and here we describe an integrated plan to systematically tap into this vast potential of fungal metabolites through genomics, metabolomics, bioactivity screening and molecular biology. In the previous funding period, we developed an untargeted approach called `metabologenomics' that correlates genomic content with metabolite output to uncover hundreds of new NPs and their gene clusters from soil actinobacteria. In this competing renewal, we now propose to extend the method to 300 fungi while integrating bioactivity screening in Aim 1. Activities described in this proposal will reduce technical barriers by establishing new workflows, improving experimental methodology, and refining scoring metrics to create a discovery platform with the ability to help unlock the medicinal potential of NPs in the fungal kingdom. In Aim 2, we focus on the targeted capture and expression of BGCs in specific euchromatic loci in a widely used host for NP heterologous expression, Aspergillus nidulans. The two Aims of the project describe the generation of genomic, metabolomics, bioactivity, and expression data. We further propose to make data- and milestone-driven progress on the combination of these complementary data types to systematically examine a set of 300 fungal strains. With a proven track record of deep collaboration among the team members involved, we will deliver a robust implementation of the proposed activities to provide a well-defined path to discovery of bioactive NP/BGC pairs, and study the production of new molecules from diverse fungi.

项目摘要/摘要 该项目的目标是改进一个基因组驱动的、基于相关性的平台，以挖掘和生产 从真菌中提取的新生物活性化合物。这一平台和研究将提供对大量真菌保存库的访问 天然产物(NPs)，历史上一直是新药和有用化合物的重要来源。 据典型估计，NPs及其衍生物约占目前使用的抗生素的75%，几乎 60%的抗癌药物以及许多抗病毒、抗寄生虫、抗真菌和免疫抑制药物 药物。尽管传统的筛查项目在历史上取得了成功，但由于 这是由于有希望的新候选人的数量不断减少，以及缺乏现成的新化合物。同时 《时代周刊》对1000多个真菌基因组的分析表明，数以万计的高价值核蛋白具有 尚待鉴定和筛选。因此，需要新的技术，在这里我们描述一个完整的计划 通过基因组学、代谢组学、生物活性系统地挖掘真菌代谢物的这一巨大潜力 筛选和分子生物学。在前一个资助期，我们开发了一种非目标方法，称为 “代谢基因组学”将基因组含量与代谢物产量联系起来，以发现数百种新的NPs 和他们来自土壤放线菌的基因簇。在这一竞争更新中，我们现在建议扩展该方法 到300个真菌，同时在AIM 1中集成生物活性筛选。本提案中描述的活动将减少 通过建立新的工作流程、改进实验方法和改进评分来设置技术障碍 创建一个发现平台的指标，能够帮助解锁真菌中NP的药用潜力 王国。在目标2中，我们重点研究了BGC在特定的常染色基因座上的靶向捕获和表达。 广泛用于NP异源表达的宿主--尼杜拉曲霉。该项目的两个目标描述了 基因组、代谢组学、生物活性和表达数据的生成。我们还建议将数据-和 在这些互补数据类型的组合方面取得里程碑式的进展，以系统地检查 一套300个真菌菌株。在相关团队成员之间进行深入合作方面有着良好的记录， 我们将对提议的活动进行可靠的实施，以提供明确定义的路径来发现 生物活性NP/BGC对，并研究从不同的真菌中产生新分子。