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Targeted Genome Mining-From Compound Discovery to Biosynthetic Pathway Elucidation.

ABSTRACT: Natural products are an important source of novel investigational compounds in drug discovery. Especially in the field of antibiotics, Actinobacteria have been proven to be a reliable source for lead structures. The discovery of these natural products with activity- and structure-guided screenings has been impeded by the constant rediscovery of previously identified compounds. Additionally, a large discrepancy between produced natural products and biosynthetic potential in Actinobacteria, including representatives of the order Pseudonocardiales, has been revealed using genome sequencing. To turn this genomic potential into novel natural products, we used an approach including the in-silico pre-selection of unique biosynthetic gene clusters followed by their systematic heterologous expression. As a proof of concept, fifteen Saccharothrixespanaensis genomic library clones covering predicted biosynthetic gene clusters were chosen for expression in two heterologous hosts, Streptomyceslividans and Streptomycesalbus. As a result, two novel natural products, an unusual angucyclinone pentangumycin and a new type II polyketide synthase shunt product SEK90, were identified. After purification and structure elucidation, the biosynthetic pathways leading to the formation of pentangumycin and SEK90 were deduced using mutational analysis of the biosynthetic gene cluster and feeding experiments with ¹³C-labelled precursors.

SUBMITTER: Gummerlich N

PROVIDER: S-EPMC7765855 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Targeted Genome Mining-From Compound Discovery to Biosynthetic Pathway Elucidation.

Gummerlich Nils N Rebets Yuriy Y Paulus Constanze C Zapp Josef J Luzhetskyy Andriy A

Microorganisms 20201219 12

Natural products are an important source of novel investigational compounds in drug discovery. Especially in the field of antibiotics, Actinobacteria have been proven to be a reliable source for lead structures. The discovery of these natural products with activity- and structure-guided screenings has been impeded by the constant rediscovery of previously identified compounds. Additionally, a large discrepancy between produced natural products and biosynthetic potential in Actinobacteria, includ ...[more]

PMID: 33352664

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Project description:Natural products (NPs) and their derivatives are a major contributor to modern medicine. Historically, microorganisms such as bacteria and fungi have been instrumental in generating drugs and lead compounds because of the ease of culturing and genetically manipulating them. However, the ever-increasing demand for novel drugs highlights the need to bioprospect previously unexplored taxa for their biosynthetic potential. Next-generation sequencing technologies have expanded the range of organisms that can be explored for their biosynthetic content, as these technologies can provide a glimpse of an organism's entire biosynthetic landscape, without the need for cultivation. The entirety of biosynthetic genes can be compared to the genes of known function to identify the gene clusters potentially coding for novel products. In this study, we mine the genomes of nine lichen-forming fungal species of the genus Umbilicaria for biosynthetic genes, and categorize the biosynthetic gene clusters (BGCs) as "associated product structurally known" or "associated product putatively novel". Although lichen-forming fungi have been suggested to be a rich source of NPs, it is not known how their biosynthetic diversity compares to that of bacteria and non-lichenized fungi. We found that 25%-30% of biosynthetic genes are divergent as compared to the global database of BGCs, which comprises 1,200,000 characterized biosynthetic genes from plants, bacteria, and fungi. Out of 217 BGCs, 43 were highly divergant suggesting that they potentially encode structurally and functionally novel NPs. Clusters encoding the putatively novel metabolic diversity comprise polyketide synthases (30), non-ribosomal peptide synthetases (12), and terpenes (1). Our study emphasizes the utility of genomic data in bioprospecting microorganisms for their biosynthetic potential and in advancing the industrial application of unexplored taxa. We highlight the untapped structural metabolic diversity encoded in the lichenized fungal genomes. To the best of our knowledge, this is the first investigation identifying genes coding for NPs with potentially novel properties in lichenized fungi.

Dataset Information

Targeted Genome Mining-From Compound Discovery to Biosynthetic Pathway Elucidation.

Publications

Targeted Genome Mining-From Compound Discovery to Biosynthetic Pathway Elucidation.

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