Synthesis, characterisation and biological evaluation of a novel library of iminosugar compounds as inhibitors of Galactofuranosyl Transferase 2 inhibitors in Mycobacterium Tuberculosis (360G-Wellcome-203974_Z_17_A)

The increasing prevalence of antimicrobial resistance (AMR) represents one of the greatest existential to humanity. Of particular concern is the emergence of multi-drug and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB) infections which significantly diminish the treatment prospects for patients. This means that there is a distinct need for novel anti-TB drugs with unique targets which will allow them to circumvent the resistance to conventional drugs. One such target is the Galactofuranosyl Transferase 2 (GalfT2) enzyme. This enzyme plays a key role in the generation of the alternating beta-1,5 and beta-1,6 furanose linkages which make up a significant portion of TB’s complex cell wall. Knock-out studies have shown that this enzyme is vital to TB viability making it an attractive drug target. Previous work in the Thomas group identified iminosugars as a weak inhibitor of GalfT2. The aim of this project is to synthesise a library of these iminosugar compounds and explore their efficacy as GalfT2 inhibitors using both whole-cell and enzyme assays. Structural elaboration will be performed, principally driven by in silico drug design which will attempt to improve the inhibitory properties. The hope of the project is to identify novel iminosugar compounds which can act as effective anti-TB compounds.