Triple drug combination screening

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The first line treatments for uncomplicated Plasmodium falciparum malaria are artemisinin-based combination therapies (ACT), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of P. falciparum isolates with decreased susceptibility to artemisinin and partner drugs presents a significant challenge to current 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 therapy (TACT). Currently, there is limited knowledge on the pharmacodynamics and pharmacogenetic interactions of proposed TACT drug combinations. As a means to evaluate these interactions, NCGC scientists have established an in vitro high-throughput assays measuring the drug dose-response to three distinct agents. 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. From this initial study, we were able to identify 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 policy decisions and evaluate next-generation TACTs.