Our primary objective is to use a blend of chemical and biological approaches to address the alarming rise in antibiotic resistance. In this endeavour, we seek to identify and characterize novel antibiotic compounds. Our approach involves genome-mining, isolation and characterization of novel natural products, and mechanistic studies of key natural product biosynthetic enzymes. Taken together, our approach aims to expedite the discovery of future medicines from biological sources. Of special interest are compounds that only kill pathogenic bacteria or directly target mechanisms of virulence. Unlike currently deployed antibiotics, which exclusively target essential life processes, our strategy holds great potential in delaying resistance. The Mitchell laboratory is a multidisciplinary team that draws methodology from the fields of chemical biology, organic chemistry, microbiology, pharmacology, structural biology, and bioinformatics.
Chris and Graham have published a paper in J. Am. Chem. Soc. along with collaborators in the Challis lab. In this paper, the YcaO proteins responsible for the installation of thiazoline and macrolactamidine in the bottromycin precursor peptide were reconstituted and their respective substrate tolerances were elucidated.
Nilkamal and Graham, along with collaborators in the van der Donk lab, have published a paper in J. Am. Chem. Soc. This paper investigates the mechanism of a radical SAM enzyme that methylates a thiazole sp2 carbon center using extensive isotope labeling and protein mutagenesis experiments.
Nilkamal has published a paper in eLife. Nilkamal, along with collaborators in the Metcalf lab, has published a paper that shows a TfuA-associated YcaO thioamides MCR, a methane-producing enzyme.
Doug will be speaking at the Natural Product Discovery and Development in the Genomic Era Conference, which will be held in Clearwater, FL from Jan. 21-24, 2018.
Graham Hudson, along with collaborators in the Nair and van der Donk labs, published a paper in PNAS. The first crystal structure of a thiopeptide [4+2] enzyme was solved with substrate-like molecules bound. Biophysical and computational methods were used to further probe the mechanistic basis for this unusual RiPP transformation. This study lays the foundation for gaining an intimate, mechanistic understanding of thiopeptide [4+2] cycloaddition.