Targeting metabolic pathways in microbial pathogens: oxidative stress and anti-folate drug resistance in trypanosomatids

The large quantity of genomic, biochemical and metabolic data on microbial pathogens provides information that helps us to select biological problems of interest and to identify targets, metabolic pathways or constituent enzymes, for therapeutic intervention. One area of potential use in developing novel anti-parasitic agents concerns the regulation of oxidative stress, and we have targeted the trypanothione peroxidase pathway in this respect. In order to characterize this pathway, we have determined crystal structures for each of its components, and are now studying enzyme–ligand complexes of the first enzyme, trypanothione reductase. Also with regard to trypanosomatids, a question that arose was: why do anti-folates not provide useful therapies? The enzyme pteridine reductase has been shown to contribute to anti-folate drug resistance, and we have determined the enzyme structure and mechanism to understand this aspect of drug resistance.