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Title: Stemming the tide of resistance in TB : development of chemical tools to evaluate mycothiol dependent enzymes in multidrug resistance in mycobacteria
Author: Rybak, Ewelina
ISNI:       0000 0004 9352 7273
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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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 the hydrophobic pocket of MST and gain some information about MST’s structure–activity relationships. The second approach involves the use of kinetic target-guided synthesis (kTGS), a process in which the protein acts as a catalyst or template in the synthesis of its own best inhibitors from the ‘choices’ provided. Towards this goal, two azido and two azidoacetamido derivatives of the simplified mycothiol analogue were successfully synthesised and can act as a handle within the binding site. Moreover, the above-mentioned azides were used to synthesize several triazoles that can be utilised as standards when kTGS is performed. The significance of these findings to future drug discovery efforts in this area is discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available