Triple drug combination screening

治疗无并发症恶性疟原虫疟疾的一线疗法是以青蒿素为基础的联合疗法（ACT），由青蒿素衍生物与作用时间较长的伴生药物联合组成。然而，对青蒿素和伴用药敏感性降低的恶性疟原虫分离株的传播对目前的疟疾控制工作构成了重大挑战。为了阻止耐药寄生虫的传播，正在评估新的化疗策略，包括实施以青蒿素为基础的三联疗法（TACT）。

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.