Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Mol Microbiol. 2011 Nov;82(4):865-78. doi: 10.1111/j.1365-2958.2011.07855.x. Epub 2011 Oct 18.
Resistance to quinoline antimalarial drugs has emerged in different parts of the world and involves sets of discrete mutational changes in pfcrt and pfmdr1 in the human malaria parasite Plasmodium falciparum. To better understand how the different polymorphic haplotypes of pfmdr1 and pfcrt contribute to drug resistance, we have conducted a linkage analysis in the F1 progeny of a genetic cross where we assess both the susceptibility and the amount of accumulation of chloroquine, amodiaquine, quinine and quinidine. Our data show that the different pfcrt and pfmdr1 haplotypes confer drug-specific responses which, depending on the drug, may affect drug accumulation or susceptibility or both. These findings suggest that PfCRT and PfMDR1 are carriers of antimalarial drugs, but that the interaction with a drug interferes with the carriers' natural transport function such that they are now themselves targets of these drugs. How well a mutant PfCRT and PfMDR1 type copes with its competing transport functions is determined by its specific sets of amino acid substitutions.
抗喹啉类抗疟药物已在世界不同地区出现，涉及人类疟原虫恶性疟原虫中 pfcrt 和 pfmdr1 的一系列离散突变变化。为了更好地了解 pfmdr1 和 pfcrt 的不同多态单倍型如何导致耐药性，我们在遗传杂交的 F1 后代中进行了连锁分析，在那里我们评估了氯喹、阿莫地喹、奎宁和奎尼丁的敏感性和积累量。我们的数据表明，不同的 pfcrt 和 pfmdr1 单倍型赋予药物特异性反应，这取决于药物，可能影响药物积累或敏感性或两者兼而有之。这些发现表明 PfCRT 和 PfMDR1 是抗疟药物的载体，但与药物的相互作用干扰了载体的自然转运功能，使它们现在成为这些药物的靶点。突变型 PfCRT 和 PfMDR1 型与其他转运功能的竞争能力取决于其特定的氨基酸取代集。
