Stemming the tide of resistance in TB: development of chemical tools to evaluate mycothiol dependent detoxification [...]

Full project title: Stemming the tide of resistance in TB: development of chemical tools to evaluate mycothiol dependent detoxification enzymes in multidrug resistance in mycobacteria

Due to the essential role that mycothiol and associated enzymes play in the protection of mycobacterial cells against toxic insults, it is hypothesized that their inhibition will impact cell viability, increase susceptibility to the host immune system and potentiate the activity of existing antibiotics. The proposed targets for this project are the mycothiol dependent detoxification enzymes mycoGlyoxalase (Rv0274) and a mycothiol-S-transferase (Rv0443). We propose to use kinetic target guided synthesis, i.e. the use of the protein of interest as a template or catalyst in the synthesis of its own best inhibitor, to discover novel chemical start points for the exploration of these new and exciting drug targets. We also aim to use this research as a platform to explore and expand the utility of kinetic target guided synthesis to streamline the early stages of drug discovery.
This research aligns with a number of key research areas, including the cross council call for innovation in the area of antimicrobial resistance and the highlighted EPSRC research areas of Chemical Biology and Biological Chemistry and Synthetic Organic Chemistry.