Triple drug combination screening

治疗非复杂恶性疟疾的一线疗法是基于青蒿素的联合疗法(ACT)，它由青蒿素衍生物和一种作用时间更长的伙伴药物组合而成。然而，对青蒿素和伙伴药物敏感性降低的恶性疟原虫分离株的传播对当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，包括实施基于青蒿素的三联疗法(TACT)。 目前，关于建议的TACT药物组合的药效学和药物遗传学相互作用的知识有限。作为评估这些相互作用的一种手段，NCGC的科学家们已经建立了一种体外高通量分析方法，测量药物对三种不同试剂的剂量反应。对来自柬埔寨的15个寄生虫品系进行了16种不同的Tact组合筛选，重点是对哌喹和青蒿素具有不同敏感性的寄生虫。分析揭示了特定遗传背景特有的药物-药物相互作用。从这项最初的研究中，我们能够识别对特定Tact敏感性降低的寄生虫基因类型，以及以依赖于基因的方式显示拮抗作用的潜在Tact。我们的化验和分析平台可以进一步被利用来为药物政策决策提供信息并评估下一代TACTS。

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.