Variations in frequencies of drug resistance in Plasmodium falciparum
Variations in frequencies of drug resistance in Plasmodium falciparum
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DOI：
10.1073/pnas.94.17.9389
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发表时间：
1997-08-19
影响因子：
11.1
通讯作者：
Lee, PC
中科院分区：
文献类型：
--
作者：
Rathod, PK;McErlean, T;Lee, PC
疟疾寄生虫种群持续暴露于不同的药物可能不仅选择了对个别药物的耐药性，而且选择了有利于启动对新的无关抗疟药物的耐药性的遗传性状。为了验证这一假设，不同的恶性疟原虫克隆具有不同数量的预先存在的耐药机制，用两种新的抗疟药：5-氟乳清酸和阿托伐醌。所有的寄生虫种群在小数量中同样敏感，然而，当这些克隆的大种群用这两种化合物中的任一种攻击时，抗性频率的显著变化变得明显。在一个极端，来自西非的克隆D 6对所有传统抗疟剂敏感，在体外简单的非诱变条件下未能产生抗性。已知对所有传统抗疟药具有抗性的印度支那克隆W2独立地获得了对两种新化合物的抗性，其频率是D 6的1,000倍。对某些（但不是全部）传统抗疟药具有抗性的其它克隆获得了对阿托伐醌的高频率抗性，但对5-氟乳清酸盐没有。基于目前对恶性疟原虫群体中耐药性演变的观点，这些发现是出乎意料和令人惊讶的。这种新的表型，称为加速耐多药（ARMD），提出了关于与疟疾寄生虫中耐药性起始相关的遗传和生化机制的重要问题。ARMD表型的一些潜在机制具有不祥的公共卫生意义。
Continual exposure of malarial parasite populations to different drugs may have selected not only for resistance to individual drugs but also for genetic traits that favor initiation of resistance to novel unrelated antimalarials. To test this hypothesis, different Plasmodium falciparum clones having varying numbers of preexisting resistance mechanisms were treated with two new antimalarial agents: 5-fluoroorotate and atovaquone. All parasite populations were equally susceptible in small numbers, However, when large populations of these clones were challenged with either of the two compounds, significant variations in frequencies of resistance became apparent, On one extreme, clone D6 from West Africa, which was sensitive to all traditional antimalarial agents, failed to develop resistance under simple nonmutagenic conditions in vitro, In sharp contrast, the Indochina clone W2, which was known to be resistant to all traditional antimalarial drugs, independently acquired resistance to both new compounds as much as a 1,000 times more frequently than D6, Additional clones that were resistant to some (but not all) traditional antimalarial agents acquired resistance to atovaquone at high frequency, but not to 5-fluoroorotate. These findings were unexpected and surprising based on current views of the evolution of drug resistance in P. falciparum populations, Such new phenotypes, named accelerated resistance to multiple drugs (ARMD), raise important questions about the genetic and biochemical mechanisms related to the initiation of drug resistance in malarial parasites, Some potential mechanisms underlying ARMD phenotypes have public health implications that are ominous.