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The primary mission of the Bachmann Lab is to apply knowledge of the design rules for secondary metabolism at the chemical, biochemical and genetic levels toward the biosynthesis of “non-natural” compounds of high value to biomedical research and the clinic. Key to this program in “synthetic biology” is the dissection of the mechanisms by which life makes bioactive molecules in vivo. The lab is organized according to three interlocking research areas: Biosynthesis, Synthetic Biology, and Discovery. These subgroups each have basic research and applied components and overlap with one another both thematically and methodologically. 1. Biosynthesis. The focus of the biosynthesis research subgroup centers on investigating the biosynthesis of pharmacophores by microorganisms from a genetic to a chemical basis. In all cases, we target non-trivial biotransformations that have little or no precedent in prior research. To date, pathways have been targeted in the bacterial Order Actinomycetales (also called actinomycetes), one of the richest microbial sources of secondary metabololites. 2. Synthetic Biology. Synthetic Biology is a burgeoning field, the ambitious aim of which is to use the machinery of biological systems (DNA, RNA, proteins) for the production of synthetic compounds and materials of high value to research, medicine and human life. For small molecule synthesis, these methods offer totally new avenues for the production of compounds and an alternative to petrochemical-based chemical synthesis. We believe that the global societal impacts of synthetic biology will be far reaching in this century. The primary mission of the Bachmann lab is to apply this knowledge of the design rules for secondary metabolism at the chemical, biochemical and genetic levels toward the biosynthesis of “non-natural” compounds of high value to bio research and the clinic. 3. Drug Discovery. It is becoming increasingly apparent that natural products derived from microbes, plants and animals represent important contributors of chemical diversity for the development of sustainable drug discovery efforts. Brian Bachmann in his former (industrial) and current (academic) lab has developed a two-pronged approach for natural product discovery: 1. A strategy for leveraging microbial genomic sequence data to predict secondary metabolic potential of microorganisms and to utilizing these predictions to prioritize isolations, accelerate isolation and structural elucidations. 2. A strategy for integrating natural product discovery into contemporary high throughput screening technologies by A) rapid generation of natural product fraction libraries from unique biological sources and B) applied metabolomics technologies for the identification and discovery of antibiotic/cytotoxic compounds. Rapid identification of compounds correlated to a biological activity of interest drives the prioritization of a classic isolation/structure-elucidation cascade in the Bachmann lab. Selected Publications Hu Y., Al-Mestarihi A., Grimes C. L., Kahne D., Bachmann B. O. A Unifying Nitrososynthase Involved in Nitrosugar Biosynthesis. Journal of The American Chemical Society. 2008, 130 (47): 15756-+. Hu, Y., Phelan, V.V., Farnet, C.M., Zazopoulos, E., and Bachmann, B.O. Reassembly of Anthramycin Biosynthetic Gene Cluster by Using Recombinogenic Cassettes. ChemBiochem. 2008 Ntai, I. and Bachmann, B.O. Identification of ACE pharmacophore in the phosphonopeptide metabolite K-26. Bioorganic and Medicinal Chemistry Letters. 2008, 18: 3068-3071. Scism, R.A., Stec, D.F., and Bachmann, B.O. Synthesis of nucleotide analogues by a promiscuous phosphoribosyltransferase. Organic Letters. 2007, 9: 4179-4182. Bachmann B.O. Foundations for directed alkaloid biosynthesis. Chemistry & Biology. 2007, 14 (8): 875-876. Hu Y., Phelan V., Ntai I., Farnet C. M., Zazopoulos E., Bachmann B. O. Benzodiazepine biosynthesis in Streptomyces refuineus. Chemistry & Biology. 2007, 14 (6): 691-701. Ntai I., Phelan VV., Bachmann B. O. Phosphonopeptide K-26 biosynthetic intermediates in Astrosporangium hypotensionis. Chemical Communications. 2006, (43): 4518-4520. Sulikowski, M., Bachmann, B. O. Developing a curriculum that goes beyond just a list of topics. ACS Chemical Biology. 2006, 1 (8): 43-45. Wilkinson B., Bachmann B. O. Biocatalysis in pharmaceutical preparation and alteration. Current Opinion in Chemical Biology. 2006, 10 (2): 169-176. McAlpine, J. B., Bachmann B.O., Piraee M., Tremblay S., Alarco A.M., Zazopoulos E., Farnet C. M. Microbial genomics as a guide to drug discovery and structural elucidation: ECO-02301, a novel antifungal agent, as an example. Journal of Natural Products. 2005, 68(4): 493-496. Ntai I., Manier M. L., Hachey D. L., Bachmann B. O. Biosynthetic origins of C-P bond containing tripeptide K-26 . Organic Letters. 2005, 7(13): 2763-2765. Zazopoulos E., Huang K. X., Staffa A., Liu W., Bachmann B. O., Nonaka K., Ahlert J., Thorson J. S., Shen B., Farnet C. M. A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nature Biotechnology. 2003, 21 (2): 187-190. Ahlert J, Shepard E, Lomovskaya N, Zazopoulos E, Staffa A, Bachmann BO, Huang KX, Fonstein L, Czisny A, Whitwam RE, Farnet CM, Thorson JS Ahlert, J.; Shepard, E.; Lomovskaya, N.; Zazopoulos, E.; Staffa, A.; Bachmann, B. O.; Huang, K.; Yang, X.; Fonstei. The calicheamicin gene cluster and its iterative type I enediyne PKS. Science. 2002, 297 (5584): 1173-1176. Miller, M. T.; Bachmann, B. O.; Townsend, C. A.; Rosenzweig, A. C. The Catalytic Cycle of b-lactam Synthetase Observed by X-ray Crystallographic Snapshots. Proceedings of the National Academy of Sciences. 2002, 12; 9923: 14752-14757. Zhou, J.; Kelly, W. L.; Bachmann, B. O.; Gunsior, M.; Townsend, C. A.; Solomon, E. I. Spectroscopic studies of substrate interactions with clavaminate synthase 2, a multifunctional alpha-KG-dependent non-heme iron enzyme: correlation with mechanisms and reactivities. Journal of the American Chemical Society. 2001, 12330: 7388-7398. Miller, M. T.; Bachmann, B. O.; Townsend, C. A.; Rosenzweig, A. C. Structure of b-lactam synthetase reveals how to synthesize antibiotics instead of asparagine. Nature Structural Biology. 2001, 8: 684-689. Bachmann, B. O.; Townsend, C. A. Kinetic Mechanism of b-lactam synthetase. Biochemistry. 2000, 3937: 11187-11193. Zhou, J.; Gunsior M.; Bachmann, B. O.; Kelly, W. L.; Pavel, E. G.; Busby, R. W.; Townsend, C. A.; Solomon, E. I. Spectroscopic studies of substrates and cosubstrate binding to the a -ketoglutarate-dependent non-heme iron enzyme clavaminate synthase 2: correlation to reactivities and mechanisms. Journal of Inorganic Biochemistry. 1999, 741 (4): 9082-9086. Specialties
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Vanderbilt University Department of Chemistry |
Assistant Professor of Chemistry