Sidhu Amar Bir Singh, Valderramos Stephanie Gaw, Fidock David A
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Mol Microbiol. 2005 Aug;57(4):913-26. doi: 10.1111/j.1365-2958.2005.04729.x.
The emergence and spread of multidrug resistant Plasmodium falciparum has severely limited the therapeutic options for the treatment of malaria. With ever-increasing failure rates associated with chloroquine or sulphadoxine-pyrimethamine treatment, attention has turned to the few alternatives, which include quinine and mefloquine. Here, we have investigated the role of pfmdr1 3' coding region point mutations in antimalarial drug susceptibility by allelic exchange in the GC03 and 3BA6 parasite lines. Results with pfmdr1-recombinant clones indicate a significant role for the N1042D mutation in contributing to resistance to quinine and its diastereomer quinidine. The triple mutations S1034C/N1042D/D1246Y, highly prevalent in South America, were also found to enhance parasite susceptibility to mefloquine, halofantrine and artemisinin. pfmdr1 3' mutations showed minimal effect on P. falciparum resistance to chloroquine or its metabolite mono-desethylchloroquine in these parasite lines, in contrast to previously published results obtained with 7G8 parasites. This study supports the hypothesis that pfmdr1 3' point mutations can significantly affect parasite susceptibility to a wide range of antimalarials in a strain-specific manner that depends on the parasite genetic background.
耐多药恶性疟原虫的出现和传播严重限制了疟疾治疗的选择。随着氯喹或磺胺多辛-乙胺嘧啶治疗失败率不断增加，人们将注意力转向了为数不多的替代药物，包括奎宁和甲氟喹。在此，我们通过在GC03和3BA6寄生虫系中进行等位基因交换，研究了pfmdr1 3'编码区点突变在抗疟药物敏感性中的作用。pfmdr1重组克隆的结果表明，N1042D突变在导致对奎宁及其非对映体奎尼丁耐药方面起重要作用。在南美洲高度流行的三重突变S1034C/N1042D/D1246Y也被发现可增强寄生虫对甲氟喹、卤泛群和青蒿素的敏感性。与先前用7G8寄生虫获得的结果相反，在这些寄生虫系中，pfmdr1 3'突变对恶性疟原虫对氯喹或其代谢产物单去乙基氯喹的耐药性影响极小。本研究支持以下假说：pfmdr1 3'点突变可根据寄生虫的遗传背景，以菌株特异性方式显著影响寄生虫对多种抗疟药物的敏感性。
