Investigation of antibiotic targets in the decaprenyl-phosphorylarabinose biosynthesis in m. tuberculosis

Tóth, Szilvia (2019). Investigation of antibiotic targets in the decaprenyl-phosphorylarabinose biosynthesis in m. tuberculosis. University of Birmingham. Ph.D.

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Abstract

An estimated 1.67 million people died of tuberculosis (TB) in 2016 and it is a threat to human life on a global-scale. To shorten current treatments and battle drug resistant strains it is important to discover and develop new drugs against the causative agent, Mycobacterium tuberculosis.
Phenotypic screens have delivered potent hit molecules in the past but the need to target new pathways in M. tuberculosis metabolism to circumvent pre-existing drug resistance mechanisms is necessary. The decaprenyl-phosphorylarabinose (DPA) biosynthetic pathway, especially the enzyme DprE1 has received much attention, however DprE2 has been overlooked as a potential drug target.
In this thesis the role of a small region of DprE1 in ligand binding and physiological function has been investigated. This region appears to interact with the substrate and based on enzyme activity assays, physiological importance of specific residues was found to be in line with the level of conservation between species.
In addition, a high-throughput screen against a DprE2 overexpressing M. bovis BCG strain has been utilised to discover new hit compounds. The screen resulted nitrofuran hit compounds that probably act as prodrugs, which was indicated by spontaneous resistant mutants resembling the mutations necessary to activate new TB pro-drug pretomanid.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):