Synthesis and evaluation of inhibitors of cell wall biosynthesis in Mycobacterium tuberculosis

May, Terry J. (2016) Synthesis and evaluation of inhibitors of cell wall biosynthesis in Mycobacterium tuberculosis. PhD thesis, University of Nottingham.

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The emergence of drug-resistant strains of tuberculosis has led to a demand for the development of new antibiotics. One new target is the cell wall biosynthesis enzyme UDP-Galp mutase (UGM), which aids the formation of the bacteria’s characteristic mycolic acid cell wall. LQ10 and LQ6 were discovered through a library screen. The synthesis of LQ10 was achieved along with 4 analogues. Another class of compounds, 2-aminothiazoles, were produced. Thirteen of these compounds were produced and along with the LQ10 analogues, initially gave encouraging results in silico.

To test their biological activity, a fluorescent probe was synthesised for use in a high-throughput fluorescence polarization (FP) assay against UDP-Galp Mutase which was expressed from E. coli. The compounds were screened using the fluorescence polarisation assay initially at a concentration of 50 µM, 9 of which demonstrated >70 % inhibition of UGM. Two of which had inhibition greater than 90 %. These preliminary results suggest that some of these compounds are, and can be developed into potent UGM inhibitors. However, it should be noted that these are only single-point results due to limitations in the quantity of UGM available, and that these will need be repeated in triplicate to determine any errors and give more reliable values.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Thomas, Neil R.
Hayes, C.J.
Keywords: drug resistance, tuberculosis, antibiotics
Subjects: Q Science > QP Physiology > QP501 Animal biochemistry
Q Science > QR Microbiology > QR 75 Bacteria. Cyanobacteria
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 35769
Depositing User: May, Terry
Date Deposited: 14 Dec 2016 06:40
Last Modified: 08 Feb 2019 08:32

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