The first-line treatments for uncomplicated Plasmodium falciparum malaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of P. falciparum 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 pharmacodynamic and pharmacogenetic interactions of proposed TACT drug combinations. To evaluate these interactions, we established an in vitro high-throughput process for measuring the drug concentration–response to three distinct antimalarial drugs present in a TACT. Sixteen different TACT combinations were screened against 15 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 plasmepsin II/III, 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.

中文翻译：

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恶性疟原虫基因型对三重青蒿素联合治疗药效学的调节

无并发症恶性疟原虫疟疾的一线治疗是基于青蒿素的联合疗法 (ACTs)，由青蒿素衍生物与长效伙伴药物组合而成。然而，对青蒿素和伙伴药物的敏感性降低的恶性疟原虫的传播对疟疾控制工作提出了重大挑战。为了阻止耐药寄生虫的传播，正在评估新的化疗策略，包括实施三重青蒿素联合疗法 (TACTs)。目前，关于拟议的 TACT 药物组合的药效学和药理学相互作用的知识有限。为了评估这些相互作用，我们建立了一个体外用于测量药物浓度 - 对 TACT 中存在的三种不同抗疟药物的反应的高通量过程。针对来自柬埔寨的 15 个寄生虫系筛选了 16 种不同的 TACT 组合，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，包括哌喹和吡咯烷之间的拮抗作用与血浆蛋白酶 II/III 的基因扩增相关，定位于寄生虫消化液泡的两种天冬氨酸蛋白酶。从这项初步研究中，我们确定了对特定 TACT 的易感性降低的寄生虫基因型，以及以基因型依赖性方式显示拮抗作用的潜在 TACT。我们的检测和分析平台可以进一步用于为药物实施决策提供信息并评估下一代 TACT。