Rathod P K, McErlean T, Lee P C
Department of Biology, The Catholic University of America, 620 Michigan Avenue, N.E., Washington, DC 20064, USA.
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9389-93. doi: 10.1073/pnas.94.17.9389.
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.
疟原虫种群持续接触不同药物，可能不仅选择了对个别药物的抗性，还选择了有利于对新型非相关抗疟药产生抗性的遗传特性。为了验证这一假设，用两种新型抗疟药5-氟乳清酸和阿托伐醌处理具有不同数量预先存在抗性机制的不同恶性疟原虫克隆。所有寄生虫种群在数量较少时同样敏感。然而，当用这两种化合物中的任何一种对这些克隆的大量种群进行挑战时，抗性频率的显著差异就变得明显了。在一个极端情况下，来自西非的克隆D6对所有传统抗疟药敏感，在体外简单的非诱变条件下未能产生抗性。形成鲜明对比的是，已知对所有传统抗疟药都有抗性的印度支那克隆W2，独立获得对这两种新化合物的抗性的频率比D6高出多达1000倍。对某些（但不是所有）传统抗疟药有抗性的其他克隆以高频率获得对阿托伐醌的抗性，但对5-氟乳清酸没有抗性。基于目前对恶性疟原虫种群耐药性进化的观点，这些发现是意想不到且令人惊讶的。这种名为对多种药物加速抗性（ARMD）的新表型，引发了关于疟原虫耐药性起始相关的遗传和生化机制的重要问题。ARMD表型背后的一些潜在机制对公共卫生有着不祥的影响。
