Multiple transporters associated with malaria parasite responses to chloroquine and quinine
Multiple transporters associated with malaria parasite responses to chloroquine and quinine
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DOI：
10.1046/j.1365-2958.2003.03627.x
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发表时间：
2003-08-01
影响因子：
3.6
通讯作者：
Su, XZ
中科院分区：
文献类型：
--
作者：
Mu, JB;Ferdig, MT;Su, XZ
已知多种转运体的突变和/或过表达可在多种生物体中产生耐药性。在疟原虫恶性疟原虫中，p -糖蛋白的同源物PfMDR1与对氯喹（CO）、奎宁（ON）和其他药物的应答有关，而一种假定的转运体PfCRT最近被证明是CO耐药的关键分子。然而，其他未知分子可能参与其中，因为携带相同pfcrt和pfmdr1等位基因的不同寄生虫克隆对CO和ON表现出广泛的定量反应。这些分子可能导致ON治疗失败的发生率增加，其分子基础尚不清楚。为了确定参与寄生虫CO和ON反应的其他基因，我们分析了97个培养适应克隆分离物对CO和ON的体外敏感性，并在编码49个推定转运体（总113 kb）的DNA和39个作为阴性对照的内控基因中寻找单核苷酸多态性（snp）。包括pfcrt和pfmdr1在内的11个可能的转运基因的snp与疟原虫对CQ和/或ON的敏感性降低有显著关联。这些基因内部和基因之间也存在显著的连锁不平衡，表明转运基因之间存在相互作用。这项研究为更好地了解疟疾寄生虫的复杂耐药性提供了具体的线索。
Mutations and/or overexpression of various transporters are known to confer drug resistance in a variety of organisms. In the malaria parasite Plasmodium falciparum, a homologue of P-glycoprotein, PfMDR1, has been implicated in responses to chloroquine (CO), quinine (ON) and other drugs, and a putative transporter, PfCRT, was recently demonstrated to be the key molecule in CO resistance. However, other unknown molecules are probably involved, as different parasite clones carrying the same pfcrt and pfmdr1 alleles show a wide range of quantitative responses to CO and ON. Such molecules may contribute to increasing incidences of ON treatment failure, the molecular basis of which is not understood. To identify additional genes involved in parasite CO and ON responses, we assayed the in vitro susceptibilities of 97 culture-adapted cloned isolates to CO and ON and searched for single nucleotide polymorphisms (SNPs) in DNA encoding 49 putative transporters (total 113 kb) and in 39 housekeeping genes that acted as negative controls. SNPs in 11 of the putative transporter genes, including pfcrt and pfmdr1, showed significant associations with decreased sensitivity to CQ and/or ON in P. faliparum. Significant linkage disequilibria within and between these genes were also detected, suggesting interactions among the transporter genes. This study provides specific leads for better understanding of complex drug resistances in malaria parasites.