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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:701194 |
| Date | January 2016 |
| Creators | May, Terry J. |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/35769/ |
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