| Job Description: |
The Shen Lab at the Department of Chemistry, the Herbert Wertheim (UF Scripps) Institute for Biomedical Innovation & Technology (https://shen.scripps.ufl.edu/), has multiple Postdoctoral Research Associate positions available immediately until filled. We are specifically looking for aspiring candidates with experience in (i) bioinformatics, genome mining, and development of enabling technologies for natural product (NP) biosynthetic gene cluster (BGC) activation in native producers or heterologous hosts, (ii) NP discovery, production, isolation, and structural elucidation, and (iii) synthetic chemistry and biocatalysis for the preparation and evaluation of antibody-drug conjugates (ADCs) as the next generation anticancer therapies by site-specific-conjugation of NPs-based payloads, such as the enediyne NPs, to the dual-variable domain (DVD)-mAbs.
Lab Overview:
Natural products (NPs) have a proven track record of success in drug discovery and development, with 66.7% of all FDA-approved new drugs between 1981-2019 that are NPs, NP derivatives, or inspired by NPs. Actinobacteria are the most extensively studied phylum for NP discovery and the most prolific sources of biologically relevant NPs, accounting for more than 60% of all characterized bacterial NPs. Progress in microbial genome sequencing and bioinformatics has fundamentally transformed the current paradigm of microbial NP discovery, providing unprecedented insights into the unexplored microbial taxa and ecological niches, and revealing the vast diversity of NP biosynthetic gene clusters (BGCs) that far exceeds the number of microbial NPs known to date. It is now possible to map the global microbial NP landscape and predict their structural complexity and rich functionality by genomics to accelerate targeted NP discovery at scale and speed, and to exploit the evolutionary intricacy of BGC regulation and expression to produce the NPs in sufficient quantities for translational evaluation and development.
The Natural Products Discovery Center (NPDC) at the Wertheim UF Scripps Institute houses one of the largest Actinobacteria strain collections in the world, totaling 122,550 strains that were isolated over the last eight decades (1940-2014) and from 77 different countries and representing microbial and NP diversities that are not available anywhere else and impossible to reproduce in laboratory settings today. We have launched a large-scale genome sequencing campaign, aiming to sequence all the strains in the collection. To date, ~26,000 strains have been sequenced, of which ~19,000 assembled genomes passed the Microbial Minimal Draft Genome criteria, representing the largest Actinobacteria genome database with the sequenced strains publicly available (https://npdc.rc.ufl.edu/home).
Current research in the Shen Lab centers on the chemistry, biochemistry, and genetics of natural product biosynthesis in Actinobacteria by leveraging the Actinobacteria Strain Collection and Genome Database at NPDC. The long-term goals of our research are to understand at a molecular level how Actinobacteria synthesize complex natural products and to exploit this knowledge to discover novel natural products to impact chemistry, enzymology, biology, and medicine. The Shen lab has been recognized as one of the world leaders in: (i) genome mining of Actinobacteria to identify privileged NP scaffolds and predict structural novelty of the new NPs, (ii) genetic manipulation of the most promising biosynthetic gene clusters (BGCs) in native producers or expression of the BGCs in designer hosts to produce and isolate the new NPs for structural and functional characterizations, (iii) investigation of the biosynthetic machinery of the new NPs to discover novel chemistry and enzymology, (iv) translation of the most promising NPs from our fundamental research as leads for drug discovery and development, and (v) establishment of the Actinobacteria Strain Collection and Genome Database Community Resource to enable NPs research and associated applications. Members of our group gain broad training spanning organic chemistry, biochemistry and enzymology, microbiology and molecular biology, and chemical biology, a qualification that is becoming essential for the modern bioorganic chemists who seek career opportunities in both academia and pharmaceutical and biotechnology industry.
Selected Recent Publications:
1. Gui, C.; Kalkreuter, E.; et al.; Shen, B. (2022) Intramolecular C-C bond formation links anthraquinone and enediyne scaffolds in tiancimycin biosynthesis. J. Am. Chem. Soc. 144: 20452-20462.
2. Steele, A.D.; Kiefer, A.F.; Hwang, D.; et al.; Shen, B. (2023) Application of a biocatalytic strategy for the preparation of tiancimycin-based antibody-drug conjugates revealing key insights into structure-activity relationships. J. Med. Chem. 66:1562-1573.
3. Gui, C.; Kalkreuter, E.; et al.; Shen, B. (2024) Cofactorless oxygenases guide anthraquinone-fused enediyne biosynthesis. Nat. Chem. Biol., 20:243-250.
4. Gui, C.; Kalkreuter, E.; et al.; Shen, B. (2024) Enediyne biosynthesis unified by a diiodotetrayne intermediate. Nat. Chem. Biol. 20:1210-1219.
5. Steele, A.D.; Meng, S.; Li, G.; et al.; Shen, B. (2024) Structural insights into the mechanism of a polyketide synthase thiocysteine lyase domain. J. Am. Chem. Soc. 146:32605-32617.
6. Kiefer, A.F.; Thirugnanasambantham, P.; et al.; Shen, B. (2025) Second generation tiancimycin-based antibody-drug conjugates enabled by highly efficient semi-synthetic approach specifically targeting non-Hodgkin’s lymphoma. J. Am. Chem. Soc. Au, ASAP online (https://doi.org/10.1021/jacsau.5c00353).
7. Kalkreuter, E.; Kautsar, S.A.; Yang, D.; Bader, C.D.; Teijaro, C.N.; et al.; Shen, B. (2024) The Natural Products Discovery Center: Release of the first 8490 sequenced strains for exploring Actinobacteria biosynthetic diversity. bioRxiv (https://www.biorxiv.org/content/10.1101/2023.12.14.571759v2).
|