Using fragment-based drug discovery to identify inhibitors of the key enzymes involved in propionate catabolism and acetate assimilation
The opportunistic human pathogen, Pseudomonas aeruginosa, is a commonly-found inhabitant in the airways of patients with chronic respiratory ailments such as COPD and cystic fibrosis (CF). Short chain fatty acids (SCFAs) such as acetate and propionate accumulate to high levels in the airways of these patients. In mutants of P. aeruginosa that are unable to catabolise SCFAs, these compounds are toxic and lead to cessation of growth. In this project, we aim to use fragment-based drug discovery to identify inhibitors of the key enzymes involved in propionate catabolism (PrpB and PrpC) and acetate assimilation (AceA). We have recently solved the x-ray crystal structure of each enzyme, and are supported by the Diamond Light Source to initiate a FBDD programme. Challenges will be to identify high affinity binders with specificity for the intended targets. Cell permeability and efflux of the “hits” will need to be investigated, as will “off target” effects, cytotoxicity to mammalian cells, and likely resistance mechanisms. Species specificity of inhibition will be examined in an in vitro polymicrobial system recently developed in the lab.