Faculty and Staff Directory
|Title:||Assistant Professor / Biochemistry and Molecular Biology
Bioorganic / Biosynthesis / Bioanalytical / Natural products chemistry and drug discovery
|Department:||Chemistry and Biochemistry
Department of Chemistry and Biochemistry
Department of Chemistry and Biochemistry
B.S., 2005, Sichuan University
M.S., 2008, Sichuan University
Ph.D., 2014, The Ohio State University
Research Areas: Bioorganic chemistry; drug discovery; genome mining; biosynthesis; biosynthetic engineering
We live in a microbial world, and those small organisms are very productive chemists. We seek to harness their tremendous chemical potential to generate structurally novel and biologically active molecules for drug discovery. We further pursue to elucidate the molecular basis for the biosynthesis of these molecules, and then use this fundamental understanding to develop new enzymes for biocatalysis, engineer biosynthetic pathways, and increase our ability to explore chemical diversity and biological activities.
Drug Discovery from Microbial Genome Mining and Metabolomics. Since the first discovery of penicillin, microbial small molecule metabolites have continued to be an essential component of drug discovery programs, especially for antibiotic and anticancer agents. Microbes harbor biosynthetic genes to encode enzymes that catalyze various chemical reactions to generate unique molecular structures. The chemical diversity and biological activity of these small molecules is virtually limitless by virtue of the abundant microbial biodiversity richness and continued evolution that can be accessed. We focus on translating this vast chemical and biological potential into opportunities for drug discovery. Our research approach is based on the opportunities that 1) a large number of unique microbial small molecules still await discovery, especially from underexplored microorganisms; 2) the exponential growth in microbial (meta)genomic data can facilitate the rapid identification of the biosynthetic genes that encode these interesting small molecules; 3) harnessing these biosynthetic genes can enable the construction of these small molecules in the laboratory; and 4) comparative metabolomics can further uniquely complement the (meta)genomic approach. Collectively, we aim to expand the microbial chemical reservoir for drug discovery.
Natural Products Biosynthesis and Bioengineering. Besides discovering new chemical entities for drug discovery, we further study the fundamental genetic and enzymatic basis underlying how microbes synthesize these molecules, especially the unique scaffolds and/or functionalities observed to be responsible for the biological activities. A subsequent application of this understanding as well as other biotechnologies allows for manipulation and reprogramming of the biosynthetic pathways to increase the chemical diversity of the products and enhance their inherent biological activities. This also provides an opportunity for the development of biocatalysts and for enabling chemoenzymatic total synthesis of important natural products, such as drug leads.
Older, E. A.; Zhang, J.; Ferris, Z. E.; Xue, D.; Zhong, Z.; Mitchell, M.; Madden, M.; Wang, Y.; Chen, H.; Nagarkatti, P.; Nagarkatti, M.; Fan, D.; Ellermann, M.; Li, Y.; Li, J. Biosynthetic Enzyme-guided Disease Correlation Connects Gut Microbial Metabolites Sulfonolipids to Inflammatory Bowel Disease Involving TLR4 Signaling. bioRxiv, 2023, DOI: https://doi.org/10.1101/2023.03.16.533047
Xue, D.; Shang, Z.; Older, E. A.; Zhong, Z.; Pulliam, C.; Peter, K.; Nagarkatti, M.; Nagarkatti, P.; Li, Y.; Li, J. Refactoring and heterologous expression of class III lanthipeptide biosynthetic gene clusters lead to the discovery of N,N-dimethylated lantibiotics from Firmicutes. ACS Chemical Biology, 2023, DOI: 10.1021/acschembio.2c00849
(Hou, L.; Tian, H.; Wang, L.; Ferris, Z. E.; Wang, J.; Cai, M.; Older, E. A.; Raja, M.; Xue, D.; Sun, W.; Nagarkatti, P.; Nagarkatti, M.; Chen, H.; Fan, D.; Tang X.; Li, J. Identification and biosynthesis of pro-inflammatory sulfonolipids from an opportunistic pathogen Chryseobacterium gleum. ACS Chemical Biology, 2022, DOI: 10.1021/acschembio.2c00141.
Xue, D.; Older, E. A.; Zhong, Z.; Shang, Z.; Chen, N.; Dittenhauser, N.; Hou, L.; Cai, P.; Walla, M.; Dong, S.; Tang, X.; Chen, H.; Nagarkatti, P.; Nagarkatti, M.; Li, Y.; Li, J. Correlational networking guides the discovery of unclustered lanthipeptide protease-encoding genes. Nature Communications, 2022, 13, 1647, DOI: 10.1038/s41467-022-29325-1
Hou, L.; Li, Y.; Wu, Q.; Li, M.; Tang, X.; Nagarkatti, P.; Nagarkatti, M.; Liu, Y.; Li, L.; Fan, D.; Bugni, T.; Shang, Z.; Li, J. Discovery of anti-infective adipostatins through bioactivity-guided isolation and heterologous expression of a type III polyketide synthase. Bioorganic Chemistry, 2021, DOI: 10.1016/j.bioorg.2021.104925
Shang, Z.; Ferris, Z.; Sweeney, D.; Chase, A.; Yuan, C.; Hui, Y.; Hou, L.; Older, E.; Xue, D.; Tang, X.; Zhang, W.; Nagarkatti, P.; Nagarkatti, M.; Testerman, T.; Jensen, P.; Li, J. Grincamycins P-T: rearranged angucycline glycosides from marine sediment-derived Streptomyces sp. CNZ-748 inhibit cell lines of the rare cancer pseudomyxoma peritonei. Journal of Natural Products, 2021, DOI: 10.1021/acs.jnatprod.1c00179
Li, Z.; Li, J.; Cai, W.; Lai, J.; McKinnie, S. M. K.; Zhang, W-P.; Moore, B. S; Zhang, W.; Qian, P. Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage. Nature Chemistry, 2019, 11, 880-889 (featured as the front cover). DOI: 10.1038/s41557-019-0317-7