Organizing Fungal Strains into a Library of Natural Products and Their Biosynthetic Gene Clusters

将真菌菌株组织成天然产物及其生物合成基因簇的文库

• 批准号: 10483096
• 负责人: Matthew Thomas Robey
• 金额: $ 25.61万
• 依托单位: ENKAY OMICS, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2023-11-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483096
• 关键词: Agriculture; Agrochemicals; Antifungal Agents; Area; Aspergillus; Atlases; Bacteria; Bioinformatics; Biological; Biological Assay; Biological Sciences; Caspofungin; Catalogs; Chemicals; Client; Collection; Complex; Computer software; Correlation Studies; Custom; Cyclosporins; Data; Data Correlations; Data Set; Development; Drug Screening; Family; Fungal Genome; Future; Gene Cluster; Genes; Genetic; Genome; Genomic approach; Genomics; Goals; Herbicides; Illinois; Industrialization; Insecticides; Lead; Letters; Libraries; Link; Lovastatin; Mass Spectrum Analysis; Medicine; Metabolism; Mining; Modern Medicine; Molecular; Molecular Biology; Natural Products; Pathway interactions; Penicillins; Penicillium; Pharmacologic Substance; Philosophy; Pilot Projects; Positioning Attribute; Predictive Value; Private Sector; Provider; Research; Research Personnel; Risk; Sampling; Secure; Services; Small Business Innovation Research Grant; Source; Surveys; Therapeutic; Work; base; bioinformatics tool; data mining; data visualization; economic value; fitness; fungus; gene discovery; genome sequencing; improved; informatics tool; interest; metabolomics; novel; novel strategies; portability; scaffold; scale up; screening; service providers; small molecule libraries; synthetic biology; trait; web app

The natural world has provided humanity with a plethora of molecules enabling major advances in modern medicine and agriculture. Fungi are one of most prolific providers of such chemicals, yet represent perhaps the most understudied source of natural products. With often >50 natural product biosynthetic gene clusters (BGCs) per strain, and only ~3% of fungal natural products known, fungi contain a wealth of new molecules ready to exploit in research. In this SBIR proposal, Enkay Omics, Inc. will refine its scalable platform (FungalMGx) to discover novel fungal natural products through a fruitful union of bioinformatics, genomics and metabolomics. We are differentiated from the handful of other startups by virtue of a “grow and go” philosophy, wherein we do not require upfront molecular or synthetic biology approaches yet can uncover hundreds of new natural scaffolds and the BGCs that produce them. This competitive advantage will be extended, protected, and used to partner with other companies to accelerate the exploitation of new natural products in the private sector. At the core of FungalMGx is the “metabologenomics” platform, previously applied to collections of >1000 strains of Actinomycete bacteria. The MGx platform involves prediction of BGCs from genome sequence data, clustering into gene cluster families (GCFs), collection of large-scale metabolomics data, and statistical correlation of gene cluster families to metabolites. However, FungalMGx is more than just applying the metabologenomics platform to fungi – through the use of our customized fungi-specific informatics tools, we will improve the precision of bioinformatic tools for BGC and GCF annotation and improve our compound discovery platform that will be portable to any strain collection of future clients and partners. This will position EnKay Omics as a leading service provider to regularize fungi into an organized chemical library for “smart” integration with bioassays conducted by future partners seeking potent “agriphores” for antifungals, insecticides, and herbicides. In this SBIR, we will de-risk the use of combined metabolomics and genomics in fungi, as this is distinct from implementation in bacteria and not been accomplished to date. Specifically, we will establish a library of fungal biosynthetic potential through the analysis of 4,000 publicly- available sequenced fungal genomes (Aim 1). Further, we use the organized set of ~150,000 gene clusters to correlate and score the metabolites detected in extracts of 140 sequenced fungal strains. In Aim 2, we develop a client-facing interface called Prospect, enabling lead prioritization and data visualization for diverse genomic and metabolomics datasets. The goal of FUNGALMGX is to establish correlative NP discovery in fungi as a viable service and position us as efficient providers of prioritized metabolites to private sector partners such as Varigen Biosciences, Clue Genetics, and “Big Ag” (e.g., Corteva Agriscience). Once refined, our unique platform and market positioning will differentiate us from other genome mining startups, and secure partnerships in the agrochemical and pharmaceutical sectors.

自然世界为人类提供了众多分子，从而实现了重大进步 现代医学和农业。真菌是此类化学物质的最多产的提供商之一， 然而，可能是最了解天然产品的来源。通常> 50天然 每个菌株的产品生物合成基因簇（BGC），仅3％的真菌天然产物 已知的真菌包含大量准备在研究中利用的新分子。在这个SBIR提案中， Enkay Omics，Inc。将完善其可扩展平台（Fungalmgx），以发现新颖的真菌天然 通过生物信息学，基因组学和代谢组学的富有成果的产品。我们是 通过“成长和走”的哲学，与少数其他创业公司区分开来，其中 我们不需要前期分子或合成生物学方法，但可以发现数百种 新的天然脚手架和生产它们的BGC。这个竞争优势将是 扩展，保护和用于与其他公司合作以加速剥削 私营部门的新天然产品。 Fungalmgx的核心是“ MetabLogeromics”平台，以前应用于 > 1000株放线菌细菌的收集。 MGX平台涉及预测 来自基因组序列数据的BGC，聚类到基因簇家族（GCF），收集 大规模代谢组学数据以及基因簇家族与代谢产物的统计相关性。 但是，Fungalmgx不仅仅是将Metablogomics平台应用于真菌 - 通过使用我们定制的真菌特定信息工具，我们将提高精度 用于BGC和GCF注释的生物信息学工具，并改善我们的复合发现平台 这将适用于未来客户和合作伙伴的任何压力集合。这将定位 OMIC是领先的服务提供商，将真菌正规化成有组织的化学图书馆 与未来合作伙伴进行的生物测定的“智能”整合，寻求潜在的“ Agriphores” 抗真菌剂，杀虫剂和除草剂。 在此SBIR中，我们将在真菌中使用合并的代谢组学和基因组学的使用，作为 这与细菌的实施不同，迄今尚未完成。具体来说， 我们将通过分析4,000张公开分析真菌生物合成潜力的库 可用的测序真菌基因组（AIM 1）。此外，我们使用了约150,000的有组织的集合 基因簇相关并评分在140个测序真菌提取物中检测到的代谢产物 菌株。在AIM 2中，我们开发了一个名为Prospect的面向客户的界面，从而实现了铅优先级 以及多种基因组和代谢组学数据集的数据可视化。 Fungalmgx的目标 是在真菌中建立相关的NP发现作为可行的服务，并将我们定位为高效 优先级代谢物的提供者向私营部门合作伙伴（例如varigen Biosciences），线索 遗传学和“大农业”（例如，Corteva Agriscience）。一旦完善，我们独特的平台和市场 定位将使我们与其他基因组采矿初创公司区分开来，并确保合作伙伴关系 农业化学和药物领域。