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

自然界为人类提供了大量的分子，使其能够取得重大进展 在现代医学和农业方面。真菌是这类化学物质最多的提供者之一， 但却代表着可能是最未被研究的天然产品来源。与经常&gt；50天然 每个菌株的产物生物合成基因簇(BGC)，只有~3%的真菌天然产物 众所周知，真菌含有丰富的新分子，随时可以在研究中加以利用。在这份SBIR提案中， Enkay Omics，Inc.将改进其可扩展平台(FungalMGx)以发现新的天然真菌 通过生物信息学、基因组学和代谢组学的卓有成效的结合来生产产品。我们是 与其他几家初创公司不同的是，它的理念是“发展壮大”，即 我们不需要预先的分子或合成生物学方法，但可以发现数百种 新的天然支架和生产它们的BGC。这种竞争优势将是 扩展、保护并用于与其他公司合作，以加快对 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 收集&gt；1000株放线菌细菌。MGX平台涉及对 来自基因组序列数据的BGC，聚成基因簇家族(GCFs)，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 这将可移植到任何未来客户和合作伙伴的压力集合中。这将使EnKay 作为领先的服务提供商，将真菌规范化为有组织的化学图书馆 与未来合作伙伴进行的生物检测的“智能”集成，以寻求有效的“农业” 抗真菌、杀虫剂和除草剂。 在这项SBIR中，我们将降低在真菌中使用联合代谢组学和基因组学的风险，因为 这与在细菌中实施不同，到目前为止还没有完成。具体来说， 我们将通过分析4000个公开的真菌生物合成潜力库- 已测序的真菌基因组(目标1)。此外，我们使用~150,000的有序集合 对140个已测序真菌提取液中检测到的代谢物进行关联和评分的基因簇 菌株。在目标2中，我们开发了一个面向客户的界面，称为展望，可实现销售线索优先排序 以及不同基因组和代谢组学数据集的数据可视化。FUNGALMGX的目标 是建立相关的真菌NP发现作为一项可行的服务，并将我们定位为高效 向Varigen Biosciences，Clue等私营部门合作伙伴提供优先代谢物 遗传学和“大农业”(如Corteva agiscience)。一旦完善，我们独特的平台和市场 定位将使我们有别于其他基因组挖掘初创公司，并确保在 农用化学品和制药部门。

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.