Plasmodium falciparum Dd2 Genome sequencing and assembly

Antimalarial drugs have thus far been derived mainly from two sources – natural products and synthetic 'drug-like' compounds. We hypothesized that antimalarial agents with novel mechanisms of action might be discovered using a diverse collection of compounds having three-dimensional features reminiscent of natural products and underrepresented in typical screening collections. We discovered such compounds with both known and novel mechanisms of action, including a series of bicyclic azetidines with activity against the blood, liver and transmission stages of the parasite life cycle. These bicyclic azetidines inhibit a novel antimalarial target, cytosolic phenylalanine-tRNA synthetase, display single low-dose cures in rodent models of Plasmodium infection, kill the blood- (asexual and sexual)- and liver-stage parasites, and have a low propensity to induce resistance in parasites. Our findings identify bicyclic azetidines with potential to cure the disease, provide prophylaxis and prevent disease transmission, and highlight the strength of diversity synthesis to reveal promising therapeutic targets.