Research
Biology-Driven Discovery
Natural products are valuable medicinal compounds which have been used to treat various human health conditions. In nature, natural products are often employed by microbes to access information about both their intracellular physiological status and their extracellular environment, and thus are critical in controlling complex processes such as chemical defense, morphological differentiation, biofilm formation, secondary metabolite production, and virulence. We aim to reveal compounds with new molecular scaffolds and functionalities that provide new drug leads or insights on the biological function of natural products in their native environment.
Li, Z., Sun, J., Du, Y., Pan, A., Zeng, L., Maboudian, R., Burne, R., Qian, P., Zhang, W. "Mutanofactin promotes adhesion and biofilm formation of cariogenic Streptococcus mutans." Nat. Chem. Biol. 2021, https://doi.org/10.1038/s41589-021-00745-2. Link Highlight in Nature Highlight in Nat. Chem. Biol.
Li, Z., Li, J., Cai, W., Lai, J. Y. H., McKinnie, S. M. K., Zhang, W., Moore, B. S., Zhang, W., Qian, P. "Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage." Nat. Chem. 2019, 11, 880-889. Link
Herman, N. A., Kim, S., Li, J. S., Cai, W., Koshino, H., Zhang, W. "The industrial anaerobe Clostridium acetobutylicum uses polyketides to regulate cellular differentiation." Nat. Commun. 2017, 8, 1514 Link
Biosynthesis and Engineering
Natural products have functional group arrays and scaffold architectures that are critical for their biological activities. By exploiting the biosynthetic machinery by which natural products are synthesized, it is possible to enhance, vary or diminish the biological activities of parent compounds and apply the biosynthetic machinery to new systems for functional group installation. We are particularly interested in biosynthesis of a few major families of natural products such as polyketides, non-ribosomal peptides, and terpenes, as well as bio-orthogonal functionalities such as alkyne, azide, and isonitrile with broad applications in chemical biology.
Del Rio Flores, A., Twigg, F. F., Du, Y., Cai, W., Aguirre, D. Q., Sato, M., Dror, M. J., Narayanamoorthy, M., Geng, J., Zill, N. A., Zhai, R., Zhang, W. "Biosynthesis of triacsin featuring an N-hydroxytriazene pharmacophore." Nat. Chem. Biol. 2021, 17, 1305-1313. Link Recommended on Faculty Opinions
Del Rio Flores, A., Kastner, D. W., Du, Y., Narayanamoorthy, M., Shen, S., Cai, W., Vennelakanti, V., Zill, N. A., Dell, L. B., Zhai, R., Kulik, H. J., Zhang, W. "Probing the Mechanism of Isonitrile Formation by a Non-Heme Iron(II)-Dependent Oxidase/Decarboxylase." J. Am. Chem. Soc. 2022, 144, 13, 5893-5901. Link Selected as JACS Cover
Porterfield, W., Poenateetai, N., Zhang, W. "Engineered Biosynthesis of Alkyne-tagged Polyketides by Type I PKSs." iScience. 2020, 23, 100938. Link Highlight in Trends in Biotechnology
Tagging and Screening
Tagging natural products with a unique chemical handle enables the visualization, enrichment, quantification, and mode of action study of natural products and advances our capabilities in natural product discovery, characterization, overproduction, and diversification. We aim to develop novel tagging methods as well as screening platforms for natural product research and beyond.
Zhu, X., Liu, J., Zhang, W. "De novo biosynthesis of terminal alkyne-labeled natural products." Nat. Chem. Biol. 2015, 11, 115-120. Link News and Views NCB's Greatest hits
Zhu, X., Shieh, P., Su, M., Bertozzi, C., Zhang, W. "A fluorogenic screening platform enables directed evolution of an alkyne biosynthetic tool." Chem. Commun. 2016, 52, 11239-11242. Link
Seidel, J., Miao, Y., Porterfield, W., Cai, W., Zhu, X., Kim, S., Hu, F., Bhattarai-Kline, S., Min, W., Zhang, W. "Structure-activity-distribution relationship study of anti-cancer antimycin-type depsipetides." Chem. Commun. 2019, 55, 9379-9382. Link
