Genome Mining in Actinobacteria via a Hybrid-Omics Discovery Platform

Tryon, James Hudson

doi:https://doi.org/10.21985/n2-7msm-4x38

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Genome Mining in Actinobacteria via a Hybrid-Omics Discovery Platform

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ABSTRACT Genome Mining in Actinobacteria via a Hybrid-Omics Discovery Platform James Hudson Tryon Natural products isolated from Actinobacteria are a vital source of medicines, agrochemicals, and commodity chemicals. The traditional, activity-driven fractionation pipelines that provided access to many of these natural products have delivered diminishing returns in recent decades. However, contemporary advancements in genome sequencing and bioinformatics have revealed vast reservoirs of untapped chemical diversity within even these commonly studied organisms. Furthermore, metagenomic studies show that many more bacterial clades exist in the environment than can currently be grown in laboratories. The almost unimaginable scale of this untapped chemical and biological diversity necessitates the development of scalable tools that will enable humanity to conceptualize, organize, and pragmatically access these systems. While genomic data has suggested potential chemical diversity, modern mass spectrometry has emerged as a complementary tool to provide direct observations of predicted compounds. We have developed a platform that aims to correlate this compound diversity to gene cluster inheritance patterns within microbial phylogenies (1). Here, this platform based upon hybridizing metabolomic and genomic data was grown and adapted to facilitate a genome mining approach for the targeted discovery of a novel cyclic arginine-incorporating natural product and its biosynthetic gene cluster (2-3). The natural product identified by this approach was rigorously connected to the targeted gene cluster family by heterologous expression. In the process, a novel biosynthetic route to a new cyclic arginine stereoisomer was identified (4). Further improvements to the tools necessary for large-scale NP 4 discovery efforts, such as the empirical testing of new bioinformatics programs and incorporation of spectral networking approaches are also described (5). In the process of these studies and method developments, greater insights into new problems and opportunities within microbial natural product space have been gained (6). Further opportunities for accessing medically relevant metabolites exist in finding pragmatic solutions for interfacing bioactivity screens of purified metabolites at efficient scales – solutions that will closely interface with automated mass spectrometry and genomic analyses in organizational capacities. Furthermore, bioinformatics and MS/MS substructure analysis tools are becoming more reliable, opening opportunities for synthetic chemists to use the preliminary structural data provided from said tools to begin total syntheses of these molecules more quickly than traditional structural studies.

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