Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone.
Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone.
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DOI：
10.1084/jem.20151519
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发表时间：
2016-06-27
期刊：
影响因子：
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通讯作者：
Ben Mamoun C
中科院分区：
文献类型：
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作者：
Lawres LA;Garg A;Kumar V;Bruzual I;Forquer IP;Renard I;Virji AZ;Boulard P;Rodriguez EX;Allen AJ;Pou S;Wegmann KW;Winter RW;Nilsen A;Mao J;Preston DA;Belperron AA;Bockenstedt LK;Hinrichs DJ;Riscoe MK;Doggett JS;Ben Mamoun C
人类巴贝斯虫病是一种蜱传多系统疾病，目前的治疗既有不良副作用，也有很大的药物失败率。Lawres等人报道，内啡肽样喹诺酮类药物与阿托伐酮联合治疗免疫缺陷小鼠的实验性巴贝斯虫病。人类巴贝斯虫病是一种由顶复虫门巴贝斯虫引起的蜱传多系统疾病。大多数巴贝斯虫病的临床病例和死亡是由微小巴贝斯虫引起的。目前人类巴贝斯虫病的治疗包括两种药物组合，阿托伐醌+阿奇霉素或奎宁+克林霉素。这些治疗与不良副作用和显著的药物失败率有关。在这里，我们提供了证据，根治实验巴贝斯虫病的免疫缺陷小鼠使用联合内啡肽样喹诺酮（ELQ）前药和阿托伐醌。使用ELQ-271、ELQ-316和ELQ-316前药ELQ-334在小鼠体内进行的功效研究表明，ELQ-316前药ELQ-334对寄生虫具有良好的生长抑制活性，其效力与口服阿托喹酮10mg /kg的效力相当。对ELQ或阿托伐醌单药治疗后复发的寄生虫进行分析，发现细胞色素bc1复合体的Qi位点或Qo位点分别出现遗传替换。令人印象深刻的是，ELQ-334和阿托伐醌联合使用，剂量低至5.0 mg/kg，导致寄生虫完全清除，在停止治疗后122天内没有复发。这些结果将为ELQ和阿托伐酮联合治疗人类巴贝斯虫病的未来临床评价奠定基础。
Human babesiosis is a tick-borne multisystem disease, and current treatments have both adverse side effects and a significant rate of drug failure. Lawres et al. report that endochin-like quinolones, in combination with atovaquone, cure experimental babesiosis in immunodeficient mice. Human babesiosis is a tick-borne multisystem disease caused by Babesia species of the apicomplexan phylum. Most clinical cases and fatalities of babesiosis are caused by Babesia microti. Current treatment for human babesiosis consists of two drug combinations, atovaquone + azithromycin or quinine + clindamycin. These treatments are associated with adverse side effects and a significant rate of drug failure. Here, we provide evidence for radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone (ELQ) prodrug and atovaquone. In vivo efficacy studies in mice using ELQ-271, ELQ-316, and the ELQ-316 prodrug, ELQ-334, demonstrated excellent growth inhibitory activity against the parasite, with potency equal to that of orally administered atovaquone at 10 mg/kg. Analysis of recrudescent parasites after ELQ or atovaquone monotherapy identified genetic substitutions in the Qi or Qo sites, respectively, of the cytochrome bc1 complex. Impressively, a combination of ELQ-334 and atovaquone, at doses as low as 5.0 mg/kg each, resulted in complete clearance of the parasite with no recrudescence up to 122 d after discontinuation of therapy. These results will set the stage for future clinical evaluation of ELQ and atovaquone combination therapy for treatment of human babesiosis.