Current antimalarial drugs cannot target all stages of the Plasmodium spp. lifecycle and are challenged by drug-resistant strains of Plasmodium falciparum. Kato et al. sought more effective drugs against this parasite by testing synthetic compounds, the structures of which were based on all of the natural products available rather than on one specific product. One series of compounds, represented by bicyclic azetidine BRD3444, was effective against a multidrug-resistant strain of P. falciparum at the blood-stage (asexual and sexual) and liver-stage of its lifecycle. Several assays revealed that BRD3444 inhibits phenylalanyl-tRNA synthetase, a previously unknown antimalarial target. Optimized analogues of BRD3444 were subsequently generated and could eliminate blood-stage and liver-stage Plasmodium berghei (a rodent malarial parasite) and P. falciparum, and prevent their transmission to mosquitoes.