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<jats:title>Abstract</jats:title><jats:p>The first-line treatments for uncomplicated <jats:italic>Plasmodium falciparum</jats:italic> malaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of <jats:italic>P. falciparum</jats:italic> with decreased susceptibility to artemisinin and partner drugs presents a significant challenge to malaria control efforts. To stem the spread of drug resistant parasites, novel chemotherapeutic strategies are being evaluated, including the implementation of triple artemisinin-based combination therapies (TACTs). Currently, there is limited knowledge on the pharmacodynamics and pharmacogenetic interactions of proposed TACT drug combinations. To evaluate these interactions, we established an <jats:italic>in vitro</jats:italic> high-throughput process for measuring the drug dose-response to three distinct antimalarial drugs present in a TACT. Sixteen different TACT combinations were screened against fifteen parasite lines from Cambodia, with a focus on parasites with differential susceptibilities to piperaquine and artemisinins. Analysis revealed drug-drug interactions unique to specific genetic backgrounds, including antagonism between piperaquine and pyronaridine associated with gene amplification of <jats:italic>plasmepsin II/III</jats:italic>, two aspartic proteases that localize to the parasite digestive vacuole. From this initial study, we identified parasite genotypes with decreased susceptibility to specific TACTs, as well as potential TACTs that display antagonism in a genotype-dependent manner. Our assay and analysis platform can be further leveraged to inform drug implementation decisions and evaluate next-generation TACTs.</jats:p><jats:sec><jats:title>One Sentence Summary</jats:title><jats:p><jats:italic>In vitro</jats:italic> process to evaluate triple-drug combinations for prioritizing antimalarial combinations for <jats:italic>in vivo</jats:italic> evaluation.</jats:p></jats:sec>

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Cold Spring Harbor Laboratory

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