Drug resistance poses a major challenge across therapeutic areas including malaria, yet factors governing resistance propensity remain poorly understood. We demonstrate that two HSP90 inhibitors targeting the identical ATP-binding site exhibit dramatically different resistance profiles in P. falciparum. Geldanamycin readily selected 10 distinct resistance mutations conferring up to 22-fold resistance,…
Mutations in the chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) in the malaria parasite . Mutant PfCRT variants, defined by the K76T substitution, mediate efflux of CQ from the parasite digestive vacuole (DV), the site of drug action. However, these mutations impair the native function of PfCRT, which…
The high burden of malaria and growing resistance to frontline antimalarials demand new drug target combinations with reduced propensities for conferring parasite resistance. An attractive approach for circumventing antimalarial drug resistance is target repurposing, in which known drugs that act through protein targets of human origin that are also active…
Cryptosporin, a fungal metabolite, exhibited potent antimalarial activity against both asexual blood stage and liver-stage with minimal human HepG2 toxicity. Unlike atovaquone, cryptosporin’s mechanism is independent of mitochondrial electron transport. Minimum inoculum of resistance showed a low risk of resistance development. RNA-Seq analysis revealed the upregulation of genes associated with…
New antimalarial drugs are needed to combat the current emergence and spread of Plasmodium falciparum parasite resistance to artemisinin-based combination therapies. Here, we characterize ZY19489, a triaminopyrimidine presently in a Phase Ib clinical trial. Asexual blood-stage parasites pressured with ZY19489 acquire low-grade resistance, mediated by a novel mutation in the…
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…
Kinases play critical roles in the development and adaptation of Plasmodium falciparum and present novel opportunities for chemotherapeutic intervention. Mitotic kinases that regulate the proliferation of the parasites by controlling nuclear division, segregation, and cytokinesis. We evaluated the potential of human Aurora kinase (Aur) inhibitors to prevent P. falciparum development…
