SELECTION FOR MEFLOQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM IS LINKED TO AMPLIFICATION OF THE PFMDR1 GENE AND CROSS-RESISTANCE TO HALOFANTRINE AND QUININE
SELECTION FOR MEFLOQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM IS LINKED TO AMPLIFICATION OF THE PFMDR1 GENE AND CROSS-RESISTANCE TO HALOFANTRINE AND QUININE
复制标题
DOI：
10.1073/pnas.91.3.1143
复制
发表时间：
1994-02-01
影响因子：
11.1
通讯作者：
THOMPSON, JK
中科院分区：
文献类型：
--
作者：
COWMAN, AF;GALATIS, D;THOMPSON, JK
两个氯喹抗性克隆分离的恶性疟原虫进行甲氟喹选择，以测试这是否会导致氯喹敏感性和pfmdr1基因扩增的改变。甲氟喹耐药株系通过这种选择被证明有扩增和过表达的pfmdr1基因及其蛋白产物（Pgh1）。编码pfmdr1的5号染色体的宏观限制图谱显示，该染色体响应于甲氟喹选择而尺寸增加，表明在该基因组区域中存在基因，该基因在甲氟喹存在下赋予选择优势。伴随着甲氟喹耐药性的增加，对卤泛群和奎宁的耐药性水平相应增加，表明真正的多药耐药表型。甲氟喹选择的寄生虫系也表现出氯喹抗性水平和pfmdr1基因拷贝数增加之间的反比关系。这些结果具有重要的意义，衍生的pfmdr1基因的扩增拷贝在现场分离，因为他们认为，奎宁压力可能参与。
Two chloroquine-resistant cloned isolates of Plasmodium falciparum were subjected to mefloquine selection to test if this resulted in alterations in chloroquine sensitivity and amplification of the pfmdr1 gene. The mefloquine-resistant lines derived by this selection were shown to have amplified and overexpressed the pfmdr1 gene and its protein product (Pgh1). Macrorestriction maps of chromosome 5, where pfmdr1 is encoded, showed that this chromosome has increased in size in response to mefloquine selection, indicating the presence of a gene(s) in this area of the genome that confers a selective advantage in the presence of mefloquine. Concomitant with the increase in mefloquine resistance was a corresponding increase in the level of resistance to halofantrine and quinine, suggesting a true multidrug-resistance phenotype. The mefloquine-selected parasite lines also showed an inverse relationship between the level of chloroquine resistance and increased pfmdr1 gene copy number. These results have important implications for the derivation of amplified copies of the pfmdr1 gene in field isolates, as they suggest that quinine pressure may be involved.