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 the Plasmodium falciparum dihydroorotate 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 against PfDHODH 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.

中文翻译：

---

对恶性疟原虫中二氢乳清酸脱氢酶抑制剂的侧支敏感性的鉴定。

据报道，每种使用的抗疟药均具有耐药性，这突出表明需要新的策略来保护正在开发的治疗剂的功效。先前我们已经证明，可以通过种群生物学陷阱抑制耐药性：通过确定对一种化合物的耐药性赋予另一种化合物超敏性（附带敏感性）的情况，我们可以设计组合疗法，不仅杀死寄生虫，还可以指导其进化远离寄生虫。反抗。我们将此概念应用于恶性疟原虫二氢乳清酸脱氢酶（PfDHODH）酶，这是一种经过验证的抗疟目标，在开发过程中具有抑制剂。在这里，我们报告了高通量筛选，以鉴定对PfDHODH抗性突变体具有特异性活性的化合物。此外，我们还进行了广泛的交叉电阻分析，从而使我们能够识别出具有互不兼容电阻潜力的化合物对。这些组合代表了利用附带敏感性以延长新的抗疟疾疗法的使用寿命的有希望的起点。