New antimalarial agents are identified and developed after extensive testing on Plasmodium falciparum parasites that can be grown in vitro . These susceptibility studies are important to inform lead optimisation and support further drug development. Until recently, little was known about the susceptibility of non-falciparum species as these had not been adapted to in vitro culture. The recent culture adaptation of P . knowlesi has therefore offered an opportunity to routinely define the drug susceptibility of this species, which is phylogenetically closer to all other human malarias than is P . falciparum. We compared the in vitro susceptibility of P . knowlesi and P . falciparum to a range of established and novel antimalarial agents under identical assay conditions. We demonstrated that P . knowlesi is significantly less susceptible than P . falciparum to six of the compounds tested; and notably these include three ATP4 inhibitors currently under development as novel antimalarial agents, and one investigational antimalarial, AN13762, which is 67 fold less effective against P . knowlesi . For the other compounds there was a less than two-fold difference in susceptibility between species. We then compared the susceptibility of a recent P . knowlesi isolate, UM01, to that of the well-established, older A1-H.1 clone. This recent isolate showed similar in vitro drug susceptibility to the A1-H.1 clone, supporting the ongoing use of the better characterised clone to further study drug susceptibility. Lastly, we used isobologram analysis to explore the interaction of a selection of drug combinations and showed similar drug interactions across species. The species differences in drug susceptibility reported by us here and previously, support adding in vitro drug screens against P . knowlesi to those using P . falciparum strains to inform new drug discovery and lead optimisation.
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