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

Tuberculosis (TB) is an infectious disease that kills more than a million people a year and poses a significant health threat. Because of the global spread of multi-drug resistant TB and high infection rates, there is a significant unmet clinical need for new drugs. M. tuberculosis (Mtb) produces mycothiol (MSH) in place of glutathione as the most abundant low molecular weight thiol. MSH and associated enzymes (e.g. mycothiol-S-transferase, MST) are thought to play pivotal roles in cellular protection against various xenobiotics. Successful synthesis of MST inhibitors may lead to the development of a novel strategy for the treatment of TB. The aim of this project is to validate MST as a novel drug target and understand the role played by MST in mycobacterial physiology via the development of MSH analogues as chemical probes. To achieve this a 2-fold approach was adopted. The first approach includes the development of mycothiol analogues. The synthetic routes towards the synthesis of three different mycothiol analogues containing glucosamine and cysteine moieties are described. These simplified analogues provide a potential scaffold for the synthesis of a library of S-conjugates that would enable us to probe ... (continues)