A Malaria Transmission-Blocking (+)-Usnic Acid Derivative Prevents Plasmodium Zygote-to-Ookinete Maturation in the Mosquito Midgut.
A Malaria Transmission-Blocking (+)-Usnic Acid Derivative Prevents Plasmodium Zygote-to-Ookinete Maturation in the Mosquito Midgut.
复制标题
一种阻断疟疾传播的 ( )-松萝酸衍生物可防止蚊子中肠中疟原虫合子到合子的成熟。
DOI：
10.1021/acschembio.6b00902
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发表时间：
2016
影响因子：
4
通讯作者：
Dinglasan,RhoelR
中科院分区：
文献类型：
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作者：
Pastrana-Mena,Rebecca;Mathias,DerrickK;Delves,Michael;Rajaram,Krithika;King,JonasG;Yee,Rebecca;Trucchi,Beatrice;Verotta,Luisella;Dinglasan,RhoelR
抗药性的演变是一个反复出现的问题，一直困扰着治疗和控制疟疾的努力。最近在东南亚出现的青蒿素耐药性突显了开发新的抗疟疾药物和在疟原虫中识别新的靶向途径的必要性。传播阻断方法通常针对宿主血流中的配子细胞或蚊子肠道中的寄生虫阶段，被公认为一种策略，当与针对红细胞期的抗疟疾药物结合使用时，不仅可以治愈疟疾，还可以防止随后的传播。我们用标准的膜喂养试验测试了从地衣中分离的代谢物(+)-松萝酸的四个衍生物对恶性疟原虫的传播阻断活性。对于两种衍生物BT37和BT122，我们观察到血粉浓度和中肠卵囊强度之间存在一致的剂量-反应关系。为了探索它们的作用机制，我们使用了伯氏疟原虫的小鼠模型，发现这两种衍生品都能阻止动细胞成熟。利用荧光显微镜，我们证明了在每个复合受精卵的存在下，活力受到了严重的影响，那些存活下来的受精卵未能伸长和成熟成动子。观察到的表型与所描述的特定激酶(NEK2/NEK4)和内膜复合体1(IMC1)蛋白的突变体相似，这两种蛋白都对受精卵到卵母细胞的转变至关重要。我们讨论了我们的发现和我们的高通量筛选方法的意义，以这些(+)-松萝酸衍生物的支架为基础，识别下一代、阻断传播的抗疟疾药物。
The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways inPlasmodiumparasites. Transmission-blocking approaches, which typically target gametocytes in the host bloodstream or parasite stages in the mosquito gut, are recognized collectively as a strategy that when used in combination with antimalarials that target erythrocytic stages will not only cure malaria but will also prevent subsequent transmission. We tested four derivatives of (+)-usnic acid, a metabolite isolated from lichens, for transmission-blocking activity againstPlasmodium falciparumusing the standard membrane feeding assay. For two of the derivatives, BT37 and BT122, we observed a consistent dose–response relationship between concentration in the blood meal and oocyst intensity in the midgut. To explore their mechanism of action, we used the murine modelPlasmodium bergheiand found that both derivatives prevent ookinete maturation. Using fluorescence microscopy, we demonstrated that in the presence of each compound zygote vitality was severely affected, and those that did survive failed to elongate and mature into ookinetes. The observed phenotypes were similar to those described for mutants of specific kinases (NEK2/NEK4) and of inner membrane complex 1 (IMC1) proteins, which are all vital to the zygote-to-ookinete transition. We discuss the implications of our findings and our high-throughput screening approach to identifying next generation, transmission-blocking antimalarials based on the scaffolds of these (+)-usnic acid derivatives.