Multi-Omics-Based Natural Product Discovery
Dr. Yi-Ming Shi
Natural products play a critical role in human health, agriculture, and veterinary medicine, as fully 30-60% of all clinically used drugs are natural products or natural product derivatives. Today, many of the most valuable drugs originate from microbial natural products, such as antibiotics penicillin and vancomycin, the immunosuppressants cyclosporin and rapamycin, anticancer drugs bleomycin and daunorubicin, and cholesterol-reducing drugs lovastatin.
Therefore, microorganisms denote excellent sources for discovering natural products with chemical diversity and structural complexity, which results in biological potency, novelty in mode of action, and selectivity in multiple applications. Nonetheless, microbes remain an under-exploited source of natural products, as the number of biosynthetic gene clusters in their genomes responsible for natural product biosyntheses far exceeds the number of compounds identified to-date. Such a predicament of natural product reseach results from a scarcity of biotechnologies to domesticate previously undomesticated microbes, as well as low efficiency approaches to express gene clusters.
To accelerate and pinpoint novel natural product discovery, we implement genomics and metabolomics, as well as throughput genetic manipulation and bioactivity assessment. By deconstructing their biosynthetic pathways in a molecular level with the assistance of analytical chemistry and biochemistry, as well as transcriptomics and proteomics, we finally aim at manipulate their biosynthetic pathways to achieve establishment of new chemical entity library.
Shi, Y.-M., Brachmann, A. O., Westphalen, M. A., Neubacher, N., Tobias, N. J. & Bode, H. B. (2019)
Dual phenazine gene clusters enable diversification during biosynthesis. Nat. Chem. Biol. 15 (4), 331-339. doi: 10.1038/s41589-019-0246-1.
Wang, G., Zhao, Z., Ke, J., Engel, Y., Shi, Y.-M., Robinson, D., Bingol, K., Zhang, Z., Bowen, B., Louie, K., Wang, B., Evans, R., Miyamoto, Y., Cheng, K., Kosina, S., De Raad, M., Silva, L., Luhrs, A., Lubbe, A., Hoyt, D. W., Francavilla, C., Otani, H., Deutsch, S., Washton, N. M., Rubin, E. M., Mouncey, N. J., Visel, A., Northen, T., Cheng, J.-F., Bode, H. B. & Yoshikuni, Y. (2019)
CRAGE enables rapid activation of biosynthetic gene clusters in undomesticated bacteria. Nat. Microbiol. 4 (12), 2498-2510. doi: 10.1038/s41564-019-0573-8.
Shi, Y.-M., Richter, C., Challinor, V. L., Grün, P., Girela del Rio, A., Kaiser, M., Schüffler, A., Piepenbring, M., Schwalbe, H. & Bode, H. B. (2018)
Georatusin, a Specific Antiparasitic Polyketide–Peptide Hybrid from the Fungus Geomyces auratus. Org. Lett. 20 (6), 1563-1567. doi: 10.1021/acs.orglett.8b00293.
Shi, Y.-M. & Bode, H. B. (2018)
Chemical language and warfare of bacterial natural products in bacteria-nematode-insect interactions. Nat. Prod. Rep.35 (4), 309-335. doi: 10.1039/c7np00054e.
Shi, Y.-M. & Bode, H. B. (2017)
Microbiology: A new language for small talk. Nat. Chem. Biol. 13 (5), 453-454. doi: 10.1038/nchembio.2362.