Effect of Fluorescent Dyes on In Vitro-Differentiated, Late-Stage Plasmodium falciparum Gametocytes
Effect of Fluorescent Dyes on In Vitro-Differentiated, Late-Stage Plasmodium falciparum Gametocytes
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DOI：
10.1128/aac.03772-14
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发表时间：
2014-12-01
影响因子：
4.9
通讯作者：
Held, Jana
中科院分区：
文献类型：
--
作者：
Gebru, Tamirat;Mordmueller, Benjamin;Held, Jana
恶性疟原虫配子体与临床症状无关，但它们负责将病原体传播给蚊子。因此，杀配子干预措施对于疟疾控制和耐药性遏制非常重要。目前可用的药物和疫苗不太适合这一目的。几种染料具有有效的抗微生物活性，但它们对配子体的使用尚未进行系统的研究。用生物发光测定法测试了9种合成染料和4种对照化合物对恶性疟原虫实验室菌株3D 7和3种临床分离株的V期配子体的杀配子活性。五种荧光染料对成熟配子体具有亚微摩尔50%抑制浓度（IC 50）值。三种线粒体染料MitoRed、碘化二己基氧碳菁（DiOC 6）和罗丹明B具有高活性（IC（50）s< 200 nM）。MitoRed对配子体显示出最高的活性，对3D 7的IC（50）为70 nM，对临床分离株的IC（50）为120 - 210 nM。所有化合物对实验室菌株3D 7比对临床分离株更有活性。特别是，内过氧化物青蒿琥酯和双氢青蒿素对3D 7的活性比对临床分离株高10倍。与所有临床使用的抗疟药相反，几种荧光染料对晚期配子体具有令人惊讶的高体外活性。由于它们也对无性血液阶段起作用，因此应将其视为开发新的抗疟先导化合物的起点。
Plasmodium falciparum gametocytes are not associated with clinical symptoms, but they are responsible for transmitting the pathogen to mosquitoes. Therefore, gametocytocidal interventions are important for malaria control and resistance containment. Currently available drugs and vaccines are not well suited for that purpose. Several dyes have potent antimicrobial activity, but their use against gametocytes has not been investigated systematically. The gametocytocidal activity of nine synthetic dyes and four control compounds was tested against stage V gametocytes of the laboratory strain 3D7 and three clinical isolates of P. falciparum with a bioluminescence assay. Five of the fluorescent dyes had submicromolar 50% inhibitory concentration (IC50) values against mature gametocytes. Three mitochondrial dyes, MitoRed, dihexyloxacarbocyanine iodide (DiOC6), and rhodamine B, were highly active (IC(50)s< 200 nM). MitoRed showed the highest activity against gametocytes, with IC(50)s of 70 nM against 3D7 and 120 to 210 nM against clinical isolates. All compounds were more active against the laboratory strain 3D7 than against clinical isolates. In particular, the endoperoxides artesunate and dihydroartemisinin showed a 10-fold higher activity against 3D7 than against clinical isolates. In contrast to all clinically used antimalarials, several fluorescent dyes had surprisingly high in vitro activity against late-stage gametocytes. Since they also act against asexual blood stages, they shall be considered starting points for the development of new antimalarial lead compounds.