Department of Infection Biology, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Veterans Affairs Medical Center, Portland, Oregon, USA.
Antimicrob Agents Chemother. 2020 Apr 21;64(5). doi: 10.1128/AAC.02549-19.
Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome complex, a target critical to the survival of both liver- and blood-stage parasites, making these drugs useful as both prophylaxis and treatment. Recently, several derivatives of endochin have been optimized to produce novel quinolones that are active and in animal models. While these quinolones exhibit potent activity against and , their activity against the zoonotic agent is unknown. We screened several of these novel endochin-like quinolones (ELQs) for their activity against and compared this with their activity against tested under identical conditions. We demonstrated that ELQs are potent against (50% effective concentration, <117 nM) and equally effective against We then screened selected quinolones and partner drugs using a longer exposure (2.5 life cycles) and found that proguanil is 10-fold less potent against than , while the quinolones demonstrate similar potency. Finally, we used isobologram analysis to compare combinations of the ELQs with either proguanil or atovaquone. We show that all quinolone combinations with proguanil are synergistic against However, against , no evidence of synergy between proguanil and the quinolones was found. Importantly, the combination of the novel quinolone ELQ-300 with atovaquone was synergistic against both species. Our data identify potentially important species differences in proguanil susceptibility and in the interaction of proguanil with quinolones and support the ongoing development of novel quinolones as potent antimalarials that target multiple species.
喹诺酮类药物，如抗疟药阿托伐醌，是疟原虫线粒体细胞色素 复合体的抑制剂，这是肝期和血期寄生虫存活的关键靶点，使这些药物成为预防和治疗的有效药物。最近，几种内啡肽的衍生物被优化，产生了新型的喹诺酮类药物，这些药物在动物模型中具有活性和。虽然这些喹诺酮类药物对 和 表现出强大的 活性，但它们对人畜共患病原虫 的活性尚不清楚。我们筛选了几种新型内啡肽样喹诺酮类药物（ELQs）对 和 的活性，并在相同条件下比较了它们对 的活性。我们证明，ELQs 对 （50%有效浓度，<117 nM）具有强大的活性，对 同样有效。然后，我们使用更长的暴露时间（2.5 个生命周期）筛选了选定的喹诺酮类药物和伙伴药物，发现丙氨嘧啶对 的效力比 低 10 倍，而喹诺酮类药物的效力相似。最后，我们使用棋盘分析比较了 ELQs 与丙氨嘧啶或阿托伐醌的组合。我们表明，ELQs 与丙氨嘧啶的所有组合对 均具有协同作用。然而，对 ，没有发现丙氨嘧啶与喹诺酮类药物之间存在协同作用的证据。重要的是，新型喹诺酮类药物 ELQ-300 与阿托伐醌的组合对这两种疟原虫均具有协同作用。我们的数据确定了丙氨嘧啶易感性和丙氨嘧啶与喹诺酮类药物相互作用方面的潜在重要种间差异，并支持新型喹诺酮类药物作为针对多种物种的有效抗疟药物的持续开发。
