Aminoacyl tRNA synthetase inhibitors
Aminoacyl t-RNA synthetases play a key role in protein synthesis acylating tRNA with the correct amino acid. Errors in this process lead to defects in protein folding and function leading to cell death. Each of the 20 amino acids has its own synthetase but some of these enzymes lack the ability to select the correct amino acid initially and are reliant on their “editing activity” to produce the correct aminoacyl-tRNA liganded product. This editing process could be disrupted and thus produce a new line of antimicrobial chemotherapy which is less likely to be overcome by resistance through mutation since these potential drugs would require simultaneous mutations in multiple genes to afford resistance.
The aim of my research is to design a probe compound which can be used to investigate selectivity between the human and bacterial forms of the seryl aminoacyl t-RNA synthetases and to further explore the potential of the probe for multi-targeting against other aminoacyl t-RNA synthetases.
The biosynthesis of the bacterial well peptidoglycan (PG) polymer has proved an invaluable target for antimicrobials, yet efficacy is endangered by resistance development. PG has no counterpart in mammalian cells minimising drug toxicity issues and provides opportunities for multi-targeting of essential proteins, reducing the risks of antimicrobial resistance (AMR) development. The formation of the PG is catalysed by a specific group of related biosynthesis enzymes termed Penicillin Binding Proteins (PBPs). The success of β-lactam antibiotics against PBPs is, in part, derived from exploitation of their common catalytic mechanism giving multi-targeting that leads to toxic cellular events. Past drug and discovery pipelines have centred on the transpeptidase activity of the PBP enzymes, but the generation of the initial glycan strand by PG-specific glycosyl transferases activities represents an additional, relatively unresourced and unexplored aspect of the activity of the same PBPs.
My aim in this project is to develop tools and reagents for the study of the glycosyl transferases. With the further aim to use fragment based drug discovery to design novel inhibitors/probes of the gylcosyl transferases.
Aminoacyl t-RNA Synthetase
Penicilin Binding Protein 1a (PBP1a)