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.
Nilkamal has published a paper in J. Am. Chem. Soc. This paper describes the in vitro reconstitution and substrate characteristics of a radical SAM methyltransferase involved in thiomuracin biosynthesis.
Brandon and Chris have published a comprehensive review in Chemical Reviews that summarizes the state of knowledge on YcaO-dependent biosynthetic pathways.
Tucker had a paper published in J. Am. Chem. Soc. In this work, an aminooxy-functionalized probe was used to discover new congeners of antipain, an NRPS-produced tetrapeptide aldehyde protease inhibitor. These efforts also identified elusive biosynthetic gene clusters, including those for chymostatin, elastatinal, and leupeptin.
Jonathan Tietz and Chris Schwalen published a paper in Nat. Chem. Biol. that describes the development of Rapid ORF Description and Evaluation Online (RODEO), a new genome-mining algorithm. Focusing on RiPPs, RODEO was used to comprehensively mine for lasso peptide gene clusters and identify the precursor peptides. RODEO was also used to guide natural product discovery efforts which uncovered six new lasso peptides, including one with a new topology. For information on RODEO, see our site for the web tool or standalone program, with tutorials, examples and more.