Mao, Weixian;
(2022)
Towards the development of inhibitors of the bacterial glyoxalase system using kinetic target guided synthesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The rise of multi drug resistant (MDR) pathogens is one of the greatest challenges we currently face. The first antibiotic was discovered in the 19 th century and resistance to existing antibacterial drugs emerged rapidly . D rugs which act via new or underexploited mechanisms of action and resistance breakers are ur gently required. Bacteria in the human body are exposed to a variety of stresses and the ability to react to and neutralise such stresses is essential for bacterial survival. ɑ K etoaldehyde methylglyoxal (MG), which bacteria produce endogenously but to which they are also exposed to in the host reacts with the nucleophilic groups in DNA, protein, and lipid s to form adducts, leading to the formation of advance d glycation end produ cts (AGEs), the degradation and inactivation of protein s and lipids and modifications to DNA. T he rapid detoxification of MG is therefore essential for bacterial survival. MG is mainly neutralized in a glutathione ( dependent manner by the action of two enzymes, G lyoxalase I (Glx I) and G lyoxalase II (Glx II). Our hypothesis is that inhibitors of the bacterial glyoxalase enzyme system could ex hibit bactericidal activity, by acting either alone or synergistic ally with existing antibiotics. To efficiently assemble inhibitors to investigate our hypothesis kinetic target guided synthesis (KTGS was employed B iased and unbiased KTGS of inhibitors towards E. coli Glx II w as carried out in collaboration with Dr Carrie A nne Molyneaux. The unbiased synthesis towards E. coli Glx I was unsuccessful after numerous attempts . However, the crystal structure of E. coli Glx I was determined to 1. 2 Å resolution and c omplexes with natural substrate (GSH) and inhibitor (Gaz) were obtained at 2.5 and 2.6 Å resolution
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Towards the development of inhibitors of the bacterial glyoxalase system using kinetic target guided synthesis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author's request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10143876 |
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