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.
Graham has published a review in Curr. Opin. Microbiol. examining the structural features, mode of action, and biosynthetic engineering capacity of several prominent antibiotic RiPP classes. .
Nilkamal and Andi, along with collaborators in the Nair lab, have published a paper in Proc. Natl. Acad. Sci. In this paper, enzymes responsible for thioamidation of ribosomal peptide backbone were investigated using extensive biochemical and structural studies.
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, Andi, and Nair lab co-workers recently published a paper in PNAS that describes the first in vitro reconstitution of peptidic thioamidation. This YcaO-dependent reaction is universal amongst methanogens, which harbor thioglycine in the active site of methyl-coenzyme M reductase. This paper elucidates the site selectivity and enzymatic mechanism of peptidic thioamidation. The crystal structure of a hyperthermophilic methanogenic YcaO was also reported. In addition to azoline and macrolactamidine formation, this report confirms thioamidation as a third type of posttranslational modification installed by members of the YcaO superfamily.