Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum
Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum
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DOI：
10.1038/35002615
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发表时间：
2000-02-24
期刊：
影响因子：
64.8
通讯作者：
Cowman, AF
中科院分区：
文献类型：
--
作者：
Reed, MB;Saliba, KJ;Cowman, AF
在整个本世纪后半叶，对用于预防和治疗最严重形式的人类疟疾的大多数一线抗疟疾药物的耐药性的产生和蔓延引起了严重的临床关切。编码恶性疟原虫P-糖蛋白同源1(Pgh1)蛋白的基因pfmdr1的多态与氯喹耐药性有关(1)；Pgh1也与对甲氟喹和氟喹啉的耐药性有关(2-5)。然而，pfmdr1与这些抗疟疾药物耐药性之间直接因果关系的确凿证据仍然难以捉摸，而且一个单一的基因杂交表明，pgh1与氯喹和甲氟喹的耐药性无关(6)。在这里，我们提供了直接证据，证明Pgh1的突变可以使人对甲氟喹、奎宁和氟喹啉产生耐药性。同样的突变以菌株特异性的方式影响寄生虫对氯喹的耐药性，以及对结构无关的化合物青蒿素的敏感性水平，这对未来抗疟疾药物的开发和疗效具有重要意义。
Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance(1); Pgh1 has also been implicated in resistance to mefloquine and halofantrine(2-5). However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine(6). Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin, This has important implications for the development and efficacy of future antimalarial agents.