Identification of Collateral Sensitivity to Dihydroorotate Dehydrogenase Inhibitors in Plasmodium falciparum.
Identification of Collateral Sensitivity to Dihydroorotate Dehydrogenase Inhibitors in Plasmodium falciparum.
复制标题
恶性疟原虫对二氢乳清酸脱氢酶抑制剂的附带敏感性的鉴定。
DOI：
10.1021/acsinfecdis.7b00217
复制
发表时间：
2018
影响因子：
5.3
通讯作者：
Lukens,AmandaK
中科院分区：
文献类型：
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作者：
Ross,LeilaSaxby;Lafuente-Monasterio,MariaJosé;Sakata-Kato,Tomoyo;Mandt,RebeccaEK;Gamo,FranciscoJavier;Wirth,DyannF;Lukens,AmandaK
据报告，每一种使用中的抗疟药都出现了耐药性，这突出表明需要制定新的战略，以保护开发中的治疗药物的功效。我们之前已经证明，耐药性可以通过群体生物学陷阱来抑制：通过确定对一种化合物的耐药性赋予对另一种化合物的超敏反应（附带敏感性）的情况，我们可以设计联合疗法，不仅杀死寄生虫，还可以引导其进化远离耐药性。我们将这一概念应用于恶性疟原虫二氢乳清酸脱氢酶（PfDHODH），这是一种经过充分验证的抗疟靶点，抑制剂正在开发中。在这里，我们报告了一个高通量筛选，以确定化合物特异性活性againstPfDHODH抗性突变体。此外，我们还进行了广泛的交叉耐药谱分析，使我们能够鉴定出具有相互不相容耐药潜力的化合物对。这些组合代表了利用附带敏感性延长新抗疟疗法有效寿命的有希望的起点。
Drug resistance has been reported for every antimalarial in use highlighting the need for new strategies to protect the efficacy of therapeutics in development. We have previously shown that resistance can be suppressed with a population biology trap: by identifying situations where resistance to one compound confers hypersensitivity to another (collateral sensitivity), we can design combination therapies that not only kill the parasite but also guide its evolution away from resistance. We applied this concept to thePlasmodium falciparumdihydroorotate dehydrogenase (PfDHODH) enzyme, a well validated antimalarial target with inhibitors in the development pipeline. Here, we report a high-throughput screen to identify compounds specifically active againstPfDHODH resistant mutants. We additionally perform extensive cross-resistance profiling allowing us to identify compound pairs demonstrating the potential for mutually incompatible resistance. These combinations represent promising starting points for exploiting collateral sensitivity to extend the useful lifespan of new antimalarial therapeutics.