Current research in Mark Zabriskie’s laboratory focuses on the biosynthesis of nonribosomal peptide and peptidyl nucleoside antibiotics. All of the compounds being studied are effective in treating various drug resistant bacterial infections and most are produced by Streptomyces spp. soil bacteria. Representative target compounds include the antitubercular agent viomycin, the antibacterial peptide enduracidin and the antifungal compound blasticidin S. Peptide natural products like enduracidin and viomycin are not synthesized by the typical ribosomal mechanism, and a main interest of the group is the biosynthetic enzymes that assemble these complex, amino acid-derived natural products. There is a particular emphasis on enzymes involved in the formation of unusual precursor amino acids and post-assembly modifications of the nascent peptides. The overarching goal in the laboratory is to gain a better understanding of the basic molecular genetics and biochemistry of these processes and then apply this knowledge toward developing novel antimicrobial agents. Our approach involves a combination of genetic and chemical methods to generate analogs that may have improved therapeutic properties.
The group also collaborates with other OSU colleagues and scientists from Indonesia to screen a collection of unique bacteria isolated from a rare Indonesian ecosystem for novel antimicrobial compounds. The bacteria are fermented in our laboratory and the extracts are screened for biological activity. The structures of the active constituents are determined, and promising lead compounds serve as the scaffold for subsequent chemical modifications to improve drug-like properties and expand chemical diversity for additional biological screening. The biosynthetic genes for compounds with exceptional activity, or which have structures suggesting novel biochemistry, may be cloned to facilitate analog development through genetic manipulation and combinatorial biosynthesis.
Fotso, S.; Zabriskie, T.M.; Proteau, P.J.; Flatt, P.M.; Santosa, D.A.; Sulastri and Mahmud, T.; Limazepines A–F, Pyrrolo[1,4]Benzodiazepine Antibiotics from an Indonesian Micrococcus sp. J. Nat. Prod. 2009, 21, In Press.
Yoon, G.S.; Zabriskie, T.M.; Cheon, S.H. Synthesis of [Guanido-13C]-γ–Hydroxyarginine. J. Label Compd. Radiopharm. 2009, 52, 53-55.
Fotso, S.; Mahmud, T.; Zabriskie, T.M.; Santosa, D.A.; Sulastri and Proteau, P.J. Rearranged and Unrearranged Angucyclinones from Indonesian Streptomyces spp. J. Antibiot. 2008, 61, 449-456.
Li, L.; Zhinan Xu, Z.; Xu, X.; Zhang, Y.; He, X.; Zabriskie, T.M. and Deng, Z.. The Mildiomycin Biosynthetic Gene Cluster: Initial steps for sequential generation of 5-hydroxymethylcytidine 5’-monophosphate and 5-hydroxymethylcytosine in Streptoverticillium rimofaciens ZJU5119. ChemBioChem, 2008, 9, 1286-94.
Fotso, S.; Mahmud, T.; Zabriskie, T.M.; Santosa, D.A.; Sulastri and Proteau, P.J. New Angucyclinones from an Indonesian Streptomyces sp. J. Nat. Prod. 2008, 71, 61-65.
Fei, X.; Yin, X.; Zhang, L. and Zabriskie, T.M. The Roles of VioG and VioQ in the Incorporation and Modification of the Capreomycidine Residue in the Peptide Antibiotic Viomycin. J. Nat. Prod. 2007, 70, 618-622.
Yin, X. and Zabriskie, T.M. The Enduracidin Biosynthetic Gene Cluster from Streptomyces fungicidicus. Microbiology, 2006, 152, 2969-2983.
Rachid, S.; Krug, D.; Kunze, B.; Kochems, I.; Scharfe, M.; Zabriskie, T.M.; Blöcker, H. and Müller, R. Molecular and biochemical studies of chondramide formation - highly cytotoxic natural products from Chondromyces crocatus Cm c5. Chem. Biol. 2006, 13, 667-681.
Grochowski, L.L. and Zabriskie, T.M. Characterization of BlsM, a Nucleotide Hydrolase Involved in Cytosine Production for the Biosynthesis of Blasticidin S. ChemBioChem 2006, 7, 957-964.
Haltli, B.; Tan, Y.; Magarvey, N.A.; Wagenaar, M.; Yin, X.; Greenstein, M.; Hucul, J. and Zabriskie, T.M. Investigating β-Hydroxyenduracididine Formation in the Biosynthesis of the Mannopeptimcyins. Chem. Biol. 2005, 12, 1163-1168.