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.
Doug will be speaking at the Outpacing Microbial Resistance sympoisum this Fall. Join the discussion on combating antimicrobial reisistance from Sept. 24-25th at UIUC.
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 JACS that redefines the thiopeptide genomic landscape. Leveraging genome-mining and RODEO, over 500 thiopeptide gene clusters were identified, representing an increase of over 350%. Harnessing this dataset, a novel thiopeptide with the rare thioamidation PTM, saalfelduracin, was identified, isolated, and characterized. Subsequently, in vivo complementation experiments were employed to demonstrate that not only is thioamidation in thiopeptides the result of TfuA/YcaO, but also “plug and play” in thiostrepton-like scaffolds.