Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity.
Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity.
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DOI：
10.7554/elife.60246
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发表时间：
2020-11-02
期刊：
影响因子：
7.7
通讯作者：
Sigala PA
中科院分区：
文献类型：
--
作者：
Okada M;Guo P;Nalder SA;Sigala PA
多西环素（DOX）是一种重要的抗疟药物，被认为是通过阻断重要顶质体细胞器中的蛋白质翻译来杀死疟原虫寄生虫。临床使用主要限于预防，因为在1-3 µM血清浓度下，第二周期寄生虫死亡延迟。DOX浓度> 5 µM可杀死具有第一周期活性的寄生虫，但被认为涉及顶质体外的脱靶机制。我们报告说，10 μM DOX在第一个周期中阻断了顶质体生物发生，并被一种必需的顶质体产物异戊烯焦磷酸拯救，证实了顶质体特异性机制。外源性铁拯救了寄生虫和顶质体生物发生，使其免受10 µM DOX的第一周期效应，而不是第二周期效应，这表明第一周期活动涉及与延迟死亡机制不同的金属依赖性机制。这些结果极大地扩展了理解DOX的基本抗寄生虫机制的范例，并建议将DOX重新用作更高剂量的更快作用的抗疟药，其多种机制预计将限制寄生虫抗性。
Doxycycline (DOX) is a key antimalarial drug thought to kill Plasmodium parasites by blocking protein translation in the essential apicoplast organelle. Clinical use is primarily limited to prophylaxis due to delayed second-cycle parasite death at 1–3 µM serum concentrations. DOX concentrations > 5 µM kill parasites with first-cycle activity but are thought to involve off-target mechanisms outside the apicoplast. We report that 10 µM DOX blocks apicoplast biogenesis in the first cycle and is rescued by isopentenyl pyrophosphate, an essential apicoplast product, confirming an apicoplast-specific mechanism. Exogenous iron rescues parasites and apicoplast biogenesis from first- but not second-cycle effects of 10 µM DOX, revealing that first-cycle activity involves a metal-dependent mechanism distinct from the delayed-death mechanism. These results critically expand the paradigm for understanding the fundamental antiparasitic mechanisms of DOX and suggest repurposing DOX as a faster acting antimalarial at higher dosing whose multiple mechanisms would be expected to limit parasite resistance.