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， 现代医学和农业。真菌是此类化学物质最多产的提供者之一， 但可能是最缺乏研究的天然产物来源。通常>50自然 每个菌株的生物合成基因簇（BGC），只有约3%的真菌天然产物 众所周知，真菌含有大量的新分子，可以用于研究。在这项SBIR提案中， Enkay Omics，Inc.将完善其可扩展的平台（FungalMGx），以发现新的真菌天然 通过生物信息学、基因组学和代谢组学的富有成效的结合，我们 与其他少数创业公司不同的是，凭借“成长和发展”的理念， 我们不需要预先的分子或合成生物学方法， 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，以前应用于 >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，聚类成基因簇家族（GCF）， 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特异性信息学工具，我们将提高 用于BGC和GCF注释的生物信息学工具，并改进我们的化合物发现平台 这将是便携式的任何应变收集未来的客户和合作伙伴。这将使EnKay Omics作为一家领先的服务提供商，将真菌规范化为一个有组织的化学库， 与未来合作伙伴进行的生物测定的“智能”集成， 抗真菌剂、杀虫剂和除草剂。 在这个SBIR中，我们将降低在真菌中使用代谢组学和基因组学组合的风险， 这不同于在细菌中的实施，并且迄今为止尚未实现。具体地说， 我们将通过分析4,000个公开的， 可用的测序真菌基因组（目的1）。此外，我们使用~ 150，000的有组织集合 基因簇，以关联和评分在140个测序真菌提取物中检测到的代谢物 菌株在目标2中，我们开发了一个名为前景的面向客户的界面，以实现潜在客户优先级排序 和数据可视化的不同基因组学和代谢组学数据集。FUNGALMGX的目标 在真菌中建立相关NP发现作为一种可行的服务，并将我们定位为高效的 向私营部门合作伙伴提供优先代谢物，如Varigen Biosciences、Clue 遗传学和“大Ag”（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，并确保在 农业化学和制药部门。