Proc. Natl Acad. Sci. USA 111, E5455–E5462 (2014)

Credit: PNAS

Malaria remains one of the largest disease burdens in humans, resulting in almost 700,000 deaths and 220 million nonfatal infections per year. For this reason, a cheaply manufactured, oral, high-efficacy drug that does not induce resistance is desperately needed. A chemical screen had identified SJ733 for further characterization as a potential preclinical compound. Jimenez-Diaz et al. now show that ex vivo, the (+)-enantiomer is significantly more potent than the racemic mixture and is active against both asexual and sexual stages; its potency and efficacy were replicated in a mouse model. The pharmacokinetics in all preclinical model species were sufficiently encouraging that it seemed this compound had the desired fast clearance component and might be a single-exposure radical cure and prophylaxis (SERCaP) drug. By sequencing drug-resistant strains, the authors identified the Na+-efflux ATPase, PfATP4, as the target of (+)-SJ733. The PfATP4 mutation caused the parasite to become less robust. Using a structural homology model, the resistance mutations were found to cluster near the ion-transporting channel in the putative drug-binding region. PfATP4 was thought to keep [Na+]i levels low, and treatment with (+)-SJ733 increases [Na+]i in the parasite. Resistance strains, however, have a higher basal [Na+]i; this may account for their poor fitness. In vivo, (+)-SJ733 promotes rapid clearance of the parasites—even faster than in infected erythrocytes. By altering cytosolic [Na+], the drug induces a stress that leads to changes in erythrocyte morphology, arrest of parasite development and eryptosis or senescence specifically in parasite-infected erythrocytes. The specificity of the drug's targeting to infected cells, the multiple changes induced in the infected host cell itself and in the parasite, the rapid clearance of either the parasite or the entire infected cell and the correlation between resistance mutations and loss of fitness make (+)-SJ733 a promising lead for front-line malaria treatment.