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Plasmodium knowlesi exhibits distinct in vitro drug susceptibility profiles from those of Plasmodium falciparum.
International Journal for Parasitology: Drugs and Drug Resistance ( IF 4 ) Pub Date : 2019-02-22 , DOI: 10.1016/j.ijpddr.2019.02.004
Donelly A van Schalkwyk 1 , Benjamin Blasco 2 , Rocio Davina Nuñez 2 , Jonathan W K Liew 3 , Amirah Amir 3 , Yee L Lau 3 , Didier Leroy 2 , Robert W Moon 1 , Colin J Sutherland 4
Affiliation  

New antimalarial agents are identified and developed after extensive testing on Plasmodium falciparum parasites that can be grown in vitro. These susceptibility studies are important to inform lead optimisation and support further drug development. Until recently, little was known about the susceptibility of non-falciparum species as these had not been adapted to in vitro culture. The recent culture adaptation of P. knowlesi has therefore offered an opportunity to routinely define the drug susceptibility of this species, which is phylogenetically closer to all other human malarias than is P. falciparum. We compared the in vitro susceptibility of P. knowlesi and P. falciparum to a range of established and novel antimalarial agents under identical assay conditions. We demonstrated that P. knowlesi is significantly less susceptible than P. falciparum to six of the compounds tested; and notably these include three ATP4 inhibitors currently under development as novel antimalarial agents, and one investigational antimalarial, AN13762, which is 67 fold less effective against P. knowlesi. For the other compounds there was a less than two-fold difference in susceptibility between species. We then compared the susceptibility of a recent P. knowlesi isolate, UM01, to that of the well-established, older A1-H.1 clone. This recent isolate showed similar in vitro drug susceptibility to the A1-H.1 clone, supporting the ongoing use of the better characterised clone to further study drug susceptibility. Lastly, we used isobologram analysis to explore the interaction of a selection of drug combinations and showed similar drug interactions across species. The species differences in drug susceptibility reported by us here and previously, support adding in vitro drug screens against P. knowlesi to those using P. falciparum strains to inform new drug discovery and lead optimisation.

中文翻译:

诺氏疟原虫表现出与恶性疟原虫不同的体外药物敏感性特征。

在对可在体外生长的恶性疟原虫寄生虫进行广泛测试后,鉴定和开发了新的抗疟药物。这些敏感性研究对于引导优化和支持进一步的药物开发非常重要。直到最近,人们对非恶性疟原虫的易感性知之甚少,因为它们尚未适应体外培养。因此,最近对诺氏疟原虫的培养适应为常规确定该物种的药物敏感性提供了机会,该物种在系统发育上比恶性疟原虫更接近所有其他人类疟疾。我们在相同的测定条件下比较了诺氏疟原虫和恶性疟原虫与一系列既定和新型抗疟药的体外敏感性。我们证明了 P. knowlesi 明显低于 P. knowlesi 易感性。恶性疟原虫对六种测试的化合物;值得注意的是,其中包括目前正在开发的三种 ATP4 抑制剂作为新型抗疟药,以及一种研究性抗疟药 AN13762,它对诺氏疟原虫的疗效降低了 67 倍。对于其他化合物,物种之间的敏感性差异不到两倍。然后,我们将最近分离的诺氏疟原虫 UM01 与成熟的较老的 A1-H.1 克隆的易感性进行了比较。这种最近的分离物显示出与 A1-H.1 克隆相似的体外药物敏感性,支持持续使用具有更好特征的克隆来进一步研究药物敏感性。最后,我们使用等效线图分析来探索选择的药物组合的相互作用,并显示出跨物种的相似药物相互作用。
更新日期:2019-11-01
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