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.

自然界为人类提供了大量的分子，推动了重大进步 在现代医学和农业方面。真菌是此类化学品最多产的提供者之一， 然而，它可能是研究最多的天然产品来源。通常>50自然 每个菌株的产物生物合成基因簇 (BGC)，仅占真菌天然产物的约 3% 众所周知，真菌含有大量可用于研究的新分子。在此 SBIR 提案中， Enkay Omics, Inc. 将完善其可扩展平台 (FungalMGx)，以发现新型天然真菌 产品通过生物信息学、基因组学和代谢组学的富有成效的结合。我们是 凭借“成长并继续”的理念，与少数其他初创公司区分开来，其中 我们不需要预先的分子或合成生物学方法，但可以发现数百个 新的天然支架和产生它们的 BGC。这种竞争优势将是 扩展、保护并用于与其他公司合作以加速开发 私营部门的新天然产品。 FungalMGx 的核心是“代谢基因组学”平台，之前应用于 超过 1000 株放线菌的集合。 MGx 平台涉及预测 来自基因组序列数据的 BGC，聚类为基因簇家族 (GCF)，收集 大规模代谢组学数据，以及基因簇家族与代谢物的统计相关性。 然而，FungalMGx 不仅仅是将代谢基因组学平台应用于真菌 – 通过使用我们定制的真菌专用信息学工具，我们将提高精确度 用于 BGC 和 GCF 注释的生物信息工具，并改进我们的化合物发现平台 这将可移植到未来客户和合作伙伴的任何菌株收集中。这将定位 EnKay Omics 作为领先的服务提供商，将真菌规范化为有组织的化学库，用于 与未来合作伙伴进行的生物测定“智能”整合，寻求有效的“agriphores” 抗真菌剂、杀虫剂和除草剂。 在此 SBIR 中，我们将降低在真菌中使用组合代谢组学和基因组学的风险，因为 这与在细菌中的实施不同，并且迄今为止尚未实现。具体来说， 我们将通过分析 4,000 个公开的真菌生物合成潜力库来建立真菌生物合成潜力库。 可用的测序真菌基因组（目标 1）。此外，我们使用约 150,000 个有组织的集合 基因簇对 140 种已测序真菌提取物中检测到的代谢物进行关联和评分 菌株。在目标 2 中，我们开发了一个名为 Prospect 的面向客户的界面，可实现潜在客户优先级排序 以及各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 发现作为一项可行的服务，并使我们成为高效的 向 Varigen Biosciences、Clue 等私营部门合作伙伴提供优先代谢物的提供商 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挖掘初创公司区分开来，并在该领域建立合作伙伴关系 农化和制药行业。