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: 10677824
• 负责人: NEIL L KELLEHER
• 金额: $ 52.79万
• 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/10677824
• 关键词: Acceleration; 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; Maps; 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; Viral; Work; Zebrafish; bioactive natural products; economic value; fungus; genome sequencing; genomic locus; immunoregulation; improved; insight; member; metabolomics; migration; neutrophil; new technology; novel; overexpression; permissiveness; response; screening; screening program; secondary metabolite; 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.

项目总结/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， 真菌中的新生物活性化合物。这个平台和研究将提供访问大量的真菌 天然产物（NPs），历史上一直是新药和有用化合物的重要来源。 典型的估计有NP及其衍生物约占。目前使用的抗生素中有75%， 60%的抗癌药物沿着众多的抗病毒、抗寄生虫、抗真菌和免疫抑制药物 药尽管他们的历史成功，传统的筛选程序已严重削减，由于 有希望的新候选药物数量减少，以及缺乏现成的新化合物。在同一 同时，对一千多个真菌基因组的分析表明，数万个高价值的NP具有 还有待鉴定和筛选因此，需要新技术，在这里我们描述了一个综合计划 通过基因组学，代谢组学，生物活性， 筛选和分子生物学。在上一个资助期，我们开发了一种非目标性方法， “代谢基因组学”，将基因组含量与代谢产物输出相关联，以发现数百种新的NP 和它们的基因簇。在这个竞争性的更新中，我们现在建议扩展该方法 对300株真菌进行了生物活性筛选。本提案所述活动将减少 通过建立新的工作流程、改进实验方法和改进评分来克服技术障碍 这些指标创建了一个发现平台，能够帮助释放真菌中NP的药用潜力。 王国在目标2中，我们关注BGC在特定常染色质基因座中的靶向捕获和表达， 广泛用于NP异源表达的宿主是构巢曲霉。该项目的两个目标描述了 基因组学、代谢组学、生物活性和表达数据的生成。我们进一步提出，使数据-和 这些互补数据类型组合的里程碑驱动进展，以系统地检查 300种真菌菌株凭借团队成员之间深入合作的良好记录， 我们将提供一个强大的实施建议的活动，以提供一个明确的路径，发现 生物活性NP/BGC配对，并研究来自不同真菌的新分子的产生。

项目成果

Discovery of the Biosynthetic Machinery for Stravidins, Biotin Antimetabolites.

斯特拉维素、生物素抗代谢物生物合成机制的发现。

• DOI: 10.1021/acschembio.9b00890
• 发表时间: 2020
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Montaser,Rana;Kelleher,NeilL
• 通讯作者: Kelleher,NeilL

Selective Targeting by a Mechanism-Based Inactivator against Pyridoxal 5'-Phosphate-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover.

• DOI: 10.1021/acs.biochem.7b00499
• 发表时间: 2017-09-19
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Mascarenhas R;Le HV;Clevenger KD;Lehrer HJ;Ringe D;Kelleher NL;Silverman RB;Liu D
• 通讯作者: Liu D

Discovery of the Tyrobetaine Natural Products and Their Biosynthetic Gene Cluster via Metabologenomics.

• DOI: 10.1021/acschembio.7b01089
• 发表时间: 2018-04-20
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Parkinson EI;Tryon JH;Goering AW;Ju KS;McClure RA;Kemball JD;Zhukovsky S;Labeda DP;Thomson RJ;Kelleher NL;Metcalf WW
• 通讯作者: Metcalf WW

Genome Mining and Metabolomics Uncover a Rare d-Capreomycidine Containing Natural Product and Its Biosynthetic Gene Cluster.

• DOI: 10.1021/acschembio.0c00663
• 发表时间: 2020-11-20
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Tryon JH;Rote JC;Chen L;Robey MT;Vega MM;Phua WC;Metcalf WW;Ju KS;Kelleher NL;Thomson RJ
• 通讯作者: Thomson RJ

Streptomyces buecherae sp. nov., an actinomycete isolated from multiple bat species.

• DOI: 10.1007/s10482-020-01493-4
• 发表时间: 2020-12
• 期刊: Antonie van Leeuwenhoek
• 作者: Hamm PS;Dunlap CA;Mullowney MW;Caimi NA;Kelleher NL;Thomson RJ;Porras-Alfaro A;Northup DE
• 通讯作者: Northup DE