Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents
Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents
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DOI：
10.1016/j.molcel.2004.09.012
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发表时间：
2004-09-24
期刊：
影响因子：
16
通讯作者：
Ward, SA
中科院分区：
文献类型：
--
作者：
Johnson, DJ;Fidock, DA;Ward, SA
恶性疟原虫的氯喹耐药性主要是由pfcrt突变引起的。对氯喹耐药的寄生虫对其他抗疟药可能表现出超敏反应;然而，交叉耐药的模式是复杂的，遗传基础仍然难以捉摸。我们发现，逐步选择金刚烷胺或卤泛群产生以前未知的pfcrt突变（包括S163 R），这与维拉帕米可逆性氯喹耐药性的损失。这是伴随着恢复有效的氯喹结合血红素在这些选定的线。这个S163 R突变提供了一个机制，PfCRT可以门质子化氯喹通过消化空泡膜的运输洞察。在东南亚分离株中存在这种突变的证据支持PfCRT在确定对结构多样的抗疟药的敏感性水平方面发挥广泛作用的论点。
Chloroquine resistance in Plasmodium falciparum is primarily conferred by mutations in pfcrt. Parasites resistant to chloroquine can display hypersensitivity to other antimalarials; however, the patterns of cross-resistance are complex, and the genetic basis has remained elusive. We show that stepwise selection for resistance to amantadine or halofantrine produced previously unknown pfcrt mutations (including S163R), which were associated with a loss of verapamil-reversible chloroquine resistance. This was accompanied by restoration of efficient chloroquine binding to hematin in these selected lines. This S163R mutation provides insight into a mechanism by which PfCRT could gate the transport of protonated chloroquine through the digestive vacuole membrane. Evidence for the presence of this mutation in a Southeast Asian isolate supports the argument for a broad role for PfCRT in determining levels of susceptibility to structurally diverse antimalarials.