Bacterial Glyoxalases as targets for drug discovery
30 June 2015
Researchers: Dr Jess Healy (project lead) and Carrie-Anne Molyneaux (PhD student)
Project description: The problem. The rise of multidrug resistance in bacterial pathogens is one of the greatest challenges currently facing medical science. To overcome this serious clinical problem novel antibacterials, which act via new or underexploited mechanisms, are of the upmost importance.
The hypothesis. A current project in our laboratory is centred on the glutathione dependent detoxification proteins Glyoxalase 1, Glyoxalase 2 and Glutathione S-transferases as novel targets for antimicrobial drug discovery. Due to the central role played by these enzymes in the protection of bacteria to a variety of ‘stresses’ we propose that inhibitors of one or all of these protein targets might exhibit bactericidal activity or act synergistically with existing antibiotics and the host immune system
To develop novel inhibitors we are currently employing kinetic target guided synthesis (kTGS) for hit/lead discovery. kTGS is an exciting addition to the medicinal chemistry tool box in which the protein of interest is used as a ‘template’ or ‘catalyst’ in the synthesis of it own best inhibitors from libraries of choices. In a case study, using Glyoxalase 2 as a model system, we have employed both a biased (utilising an azido derivative of the peptide substrate glutathione) and an unbiased fragment based approach. This has resulted in the identification of a number of novel hit compounds and work is ongoing to synthesise and validate these hits. This project also provides an ideal platform for the further development of the kTGS methodology. Towards this aim we are currently investigating additional reactions to expand the chemical repertoire available for kTGS.
Future work will apply this methodology to Glyoxalase 1 and a subset of Gluathione-S-transferases. With a robust toolbox of inhibitors in hand we can then begin to challenge our working hypothesis.
Funding: UCL School of Pharmacy
Contact: Dr Jess Healy