Targeting Plasmodium falciparum Coenzyme-A biosynthesis for clinical development of novel selective antimalarials
Efficiency of antimalarial treatments is under constant pressure due to fast emergence of resistant parasites. One reason is that most available drugs solely target the fast replicating blood stages. Hence, through our focus on parasite biology during host switching, we anticipate to identify novel potential prophylactic and transmission-blocking drug targets. In a large public-private and transatlantic collaboration, we have synthesized potent antimalarials that target asexual and sexual blood-stage parasites. Using CRISPR-Cas9-based approaches, my PhD student Laura de Vries has provided evidence for their mechanism of action. Our data suggest that drug-derived CoA analogues act as antimetabolites that target acetyl-CoA synthetase thereby inhibiting the conversion of CoA to acetyl-CoA. Current studies are focussing on drug resistance profiles and the mechanism of action of these pantothenamides during transmission.