Thesis

Development of novel inhibitors of carbohydrate-processing targets involved in Mycobacterium tuberculosis cell wall biosynthesis

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2016
Thesis identifier
  • T15196
Person Identifier (Local)
  • 201288965
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Tuberculosis (TB) remains one of the world's most lethal infectious diseases. The emergence and increasing prevalence of drug-resistant strains of Mycobacterium tuberculosis (M.tb) highlights the urgent need for new antitubercular medicines. Decaprenylphosphoryl-β-D-ribose 2'-epimerase 1 (DprE1) and N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) are two recently characterised carbohydrate-processing enzymes essential for M.tb cell wall biosynthesis, both of which have promising potential as targets for new TB therapies. This thesis describes efforts to identify inhibitors of DprE1 and GlmU as possible new drug candidates for the treatment of TB, or as tool compounds to help develop a wider understanding of these novel targets. Chapters 1-3 introduce TB, physicochemical properties and their application in drug discovery, and DprE1 respectively. Chapters 4-6 detail hit-to-lead investigations around two compounds identified in a DprE1 high throughput screening (HTS) campaign. Hit validation was performed first, then each hit was expanded into a lead series, delineating structure-activity-relationships and identifying exemplars that displayed both high potency at DprE1 and against M.tb in vitro (with demonstrable engagement at DprE1). An overall aspiration was to identify DprE1 inhibitors that had high potential to succeed as new medicines for TB; as such, physicochemical properties were at the forefront of the molecular design strategy in these Chapters. Chapter 7 details the design, synthesis and biological evaluation of DprE1 inhibitors based on the natural substrate of the enzyme. This work focussed on investigating whether such ribose-based structures could provide a hydrophilic start-point from which to develop potent DprE1 inhibitors. These substrate analogues were also used as tool compounds to probe interactions between DprE1 and small molecule inhibitors, and to provide insight into the nature of the enzyme-catalysed reaction.Chapter 8 of this thesis introduces the second M.tb target, GlmU. Chapter 9 outlines the design and synthesis of a small set of GlmU acetyltransferase inhibitors based on the substrate of the enzyme. In the absence of any quality literature M.tb GlmU inhibitors, this work provided chemical matter to help establish the recently developed GSK M.tb GlmU acetyltransferase enzyme assay. Finally, Chapter 10 reflects on the work presented in this thesis, and offers some perspectives for the future of tuberculosis drug discovery.
Advisor / supervisor
  • Burley, Glenn
Resource Type
Note
  • Previously held under moratorium in Chemistry Department (GSK) from 19th May 2016 until 19th May 2018.
DOI
Date Created
  • 2016
Former identifier
  • 9912708385902996
Funder

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