Drug resistance is a widespread problem across therapeutic areas including malaria, but what accounts for resistance propensity remains poorly understood. Here, we reveal that two HSP90 inhibitors targeting the identical ATP-binding site exhibit dramatically different resistance profiles in . Geldanamycin readily selected 10 distinct resistance mutations conferring up to 22-fold…
Plasmodium falciparum evades the antimalarial activity of proline-competitive prolyl-tRNA synthetase (PfProRS) inhibitors, such as halofuginone (HFG), by a resistance mechanism termed the adaptive proline response (APR). The APR is characterized by a marked elevation of intracellular proline following drug exposure. Contrary to initial expectations, the APR is not mediated by…
New antimalarial drugs are essential to combat the current emergence and spread of parasite resistance to first-line artemisinin-based combination therapies. Here, we identify a mechanism of parasite resistance to ZY19489, a triaminopyrimidine currently in a Phase IIb clinical trial. Low-grade resistance was mediated by a novel mutation in the chloroquine…
The identification of novel antimalarials with activity against both the liver and blood stages of the parasite lifecycle would have the dual benefit of prophylactic and curative potential. However, one challenge of leveraging chemical hits from phenotypic screens is subsequent target identification. Here, we use evolution of resistance to investigate…
The decline in malaria deaths has recently stalled owing to several factors, including the widespread resistance of Anopheles vectors to the insecticides used in long-lasting insecticide-treated nets (LLINs). One way to mitigate insecticide resistance is to directly kill parasites during their mosquito-stage of development by incorporating antiparasitic compounds into LLINs.
The high burden of malaria and growing resistance to frontline antimalarials demand new drugs with reduced propensities for generating resistance. An attractive approach to identifying chemical hits as starting points for antimalarial drug discovery involves the repositioning and chemical optimization of compounds used in other disease areas that are active…
Kinase inhibitors are potent therapeutics, but most essential Plasmodium kinases remain unexploited as antimalarial targets. We identified compound 12, a type II kinase inhibitor based on aminopyridine and 2,6-benzimidazole scaffolds, as a lead compound with nanomolar potency, fast action, and in vivo activity in the Plasmodium berghei rodent malaria model.
Identification of novel drug targets is a key component of modern drug discovery. While antimalarial targets are often identified through the mechanism of action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space is also constrained by existing compound libraries and phenotypic…
