Malaria drug resistance is associated with defective DNA mismatch repair
Malaria drug resistance is associated with defective DNA mismatch repair
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DOI：
10.1016/j.molbiopara.2011.02.004
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发表时间：
2011-06-01
影响因子：
1.5
通讯作者：
Taraschi, Theodore F.
中科院分区：
文献类型：
--
作者：
Castellini, Meryl A.;Buguliskis, Jeffrey S.;Taraschi, Theodore F.
疟疾寄生虫表现出惊人的遗传可塑性，其标志之一是对新药的耐药率不断增加，特别是在东南亚，那里的多重耐药（MDR）威胁着最后一线抗疟药物青蒿琥酯化合物。以往的研究量化了对多种药物的加速耐药（ARMD）现象，但其基本机制尚不清楚。我们利用前向遗传分析来研究一种新的假设，即DNA错配修复缺陷（MMR）有助于恶性疟原虫MDR的发展。我们报告了两种ARMD寄生虫，W2和Dd2，以及氯喹抗性寄生虫T9-94, 7C12和7G8具有缺陷的MMR。而对氯喹敏感的寄生虫HB3、D6和3D7则是MMR熟练的。有趣的是，W2无法修复位于3'的链断裂的底物，这是由于观察到PfMutL α含量的大量减少。这些数据表明，MMR缺陷可能导致抗疟药耐药性。(C) 2011 Elsevier B.V.版权所有
Malarial parasites exhibit striking genetic plasticity, a hallmark of which is an ever-increasing rate of resistance to new drugs, especially in Southeast Asia where multi-drug resistance (MDR) threatens the last line of antimalarial drugs, the artesunate compounds. Previous studies quantified the accelerated resistance to multiple drugs (ARMD) phenomenon, but the underpinning mechanism(s) remains unknown. We utilize a forward genetic assay to investigate a new hypothesis that defective DNA mismatch repair (MMR) contributes to the development of MDR by Plasmodium falciparum parasites. We report that two ARMD parasites, W2 and Dd2, have defective MMR, as do the chloroquine-resistant parasites T9-94, 7C12, and 7G8. By contrast, the chloroquine-sensitive parasites HB3, D6 and 3D7 were MMR proficient. Interestingly, W2 was unable to repair substrates with a strand break located 3' to the mismatch, which is attributable to a large observed decrease in PfMutL alpha content. These data imply that antimalarial drug resistance can result from defective MMR. (C) 2011 Elsevier B.V. All rights reserved.