Integrative omics for the discovery of novel natural products
Speaker: Tilmann Weber (DTU)
Host: Evi Stegmann (Universität Tübingen)
Date & Time: 13.02.2024 | 12:30 – 2 pm
Venue: A3M04
Abstract:
The genetic potential of microorganisms to synthesize specialized metabolites by far exceeds the number of experimentally observed molecules. With decreased costs of obtaining high-quality genome sequences, in silico genome mining has become an indispensable tool to complement the classical chemistry-centered approach to identify and characterize novel secondary / specialized metabolites. Bioinformatics platforms, such as the open-source genome mining pipeline antiSMASH (https://antismash.secondarymetabolites.org), which we develop in collaboration with the group of M. Medema (U. Wageningen, Netherlands) give us convenient access to assess the genetic potential of microbial producers of natural products. Extensions, like the BGCFlow workflow1 allow to perform comprehensive studies on hundreds to (ten)thousands of genomes.
In order to make practical use of these in silico obtained data, efficient engineering approaches for the specialized metabolite producers, in our case filamentous actinomycetes, are required. We have therefore developed an extensive CRISPR-based toolkit for streptomycetes. Latest additions to the toolkit are a system to highly multiplex CRISPR experiments2 or use an optimized Cas3-based system instead the commonly used Streptococcus pyogenes Cas9.3
These tools allowed us to identify and characterize various novel BGCs in actinomycetes such as the gargantulide4 or pteridic acids BGCs5.
References
1. Nuhamunada, M., Mohite, O.S., Phaneuf, P.V., Palsson, B., and Weber, T. (2023). BGCFlow: Systematic pangenome workflow for the analysis of biosynthetic gene clusters across large genomic datasets. bioRxiv DOI: doi.org/10.1101/2023.06.14.545018.
2. Whitford, C.M., Gren, T., Palazzotto, E., Lee, S.Y., Tong, Y., and Weber, T. (2023). Systems Analysis of Highly Multiplexed CRISPR-Base Editing in Streptomycetes. ACS Synth Biol 12, 2353-2366. 10.1021/acssynbio.3c00188.
3. Whitford, C.M., Gockel, P., Faurdal, D., Gren, T., Sigrist, R., and Weber, T. (2023). CASCADE-Cas3 Enables Highly Efficient Genome Editing in Streptomyces species. bioRxiv DOI: doi.org/10.1101/2023.05.09.539971.
4. Carretero-Molina, D., Ortiz-López, F.J., Gren, T., Oves-Costales, D., Martín, J., Román-Hurtado, F., Sparholt Jørgensen, T., de la Cruz, M., Díaz, C., Vicente, F., et al. (2022). Discovery of gargantulides B and C, new 52-membered macrolactones from Amycolatopsis sp. Complete absolute stereochemistry of the gargantulide family. Organic Chemistry Frontiers 9, 462-470. 10.1039/d1qo01480c.
5. Yang, Z., Qiao, Y., Konakalla, N.C., Strobech, E., Harris, P., Peschel, G., Agler-Rosenbaum, M., Weber, T., Andreasson, E., and Ding, L. (2023). Streptomyces alleviate abiotic stress in plant by producing pteridic acids. Nat. Commun. 14, 7398. 10.1038/s41467-023-43177-3.