Ansbro Megan R, Itkin Zina, Chen Lu, Zahoranszky-Kohalmi Gergely, Amaratunga Chanaki, Miotto Olivo, Peryea Tyler, Hobbs Charlotte V, Suon Seila, Sá Juliana M, Dondorp Arjen M, van der Pluijm Rob W, Wellems Thomas E, Simeonov Anton, Eastman Richard T
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
Wellcome Sanger Institute, Hinxton CB10 1SA, U.K.
ACS Pharmacol Transl Sci. 2020 Nov 2;3(6):1144-1157. doi: 10.1021/acsptsci.0c00110. eCollection 2020 Dec 11.
The first-line treatments for uncomplicated malaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of 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 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 , 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.
单纯性疟疾的一线治疗方法是青蒿素联合疗法（ACTs），该疗法由一种青蒿素衍生物与一种作用时间更长的辅助药物组成。然而，对青蒿素和辅助药物敏感性降低的情况不断蔓延，这给疟疾防控工作带来了重大挑战。为了遏制耐药寄生虫的传播，人们正在评估新的化疗策略，包括采用三联青蒿素联合疗法（TACTs）。目前，对于拟用的TACT药物组合的药效学和药物遗传学相互作用了解有限。为了评估这些相互作用，我们建立了一个高通量流程，用于测量对TACT中三种不同抗疟药物的药物浓度反应。针对来自柬埔寨的15种寄生虫株筛选了16种不同的TACT组合，重点关注对哌喹和青蒿素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相互作用，包括哌喹和咯萘啶之间的拮抗作用，这与定位于寄生虫消化液泡的两种天冬氨酸蛋白酶的基因扩增有关。从这项初步研究中，我们确定了对特定TACT敏感性降低的寄生虫基因型，以及以基因型依赖方式表现出拮抗作用的潜在TACT。我们的检测和分析平台可进一步用于为药物应用决策提供信息，并评估下一代TACT。
