Role of the ABC transporter MRPA (PGPA) in antimony resistance in Leishmania infantum axenic and intracellular amastigotes
Role of the ABC transporter MRPA (PGPA) in antimony resistance in Leishmania infantum axenic and intracellular amastigotes
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DOI：
10.1128/aac.49.5.1988-1993.2005
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发表时间：
2005-05-01
影响因子：
4.9
通讯作者：
Oullette, M
中科院分区：
文献类型：
--
作者：
El Fadili, K;Messier, N;Oullette, M
锑化合物是治疗原生动物寄生虫利什曼原虫感染的主要药物。我们提出了我们的研究婴儿利什曼原虫无鞭毛体寄生虫选择的抗酒石酸锑钾[Sb（III）]。在巨噬细胞内，Sb（III）选择的细胞对葡萄糖酸锑钠（Pentoclutamine）具有交叉耐药性，这是用于对抗利什曼原虫的主要药物。使用定制的DNA微阵列比较了易感和耐药无鞭毛体之间40多个基因表达水平的假定改变。ABC转运蛋白MRPA（PGPA），S-腺苷高半胱氨酸水解酶，和folylpolyglutamate合成酶编码的三个基因的表达被认为是一致的增加。发现突变体中半胱氨酸的水平增加。MRPA基因的转染显示出在细胞内寄生虫中赋予葡萄糖酸锑钠抗性。这种MRPA介导的耐药性可以通过使用谷胱甘肽生物合成特异性抑制剂丁硫堇磺酰亚胺来逆转。这些结果首次强调了MRPA在寄生虫无鞭毛体阶段的锑抗性中的作用，并提出了逆转抗性的策略。
Antimonial compounds are the mainstay for the treatment of infections with the protozoan parasite Leishmania. We present our studies on Leishmania infantum amastigote parasites selected for resistance to potassium antimonyl tartrate [Sb(III)]. Inside macrophages, the Sb(III)-selected cells are cross-resistant to sodium stibogluconate (Pentostam), the main drug used against Leishmania. Putative alterations in the level of expression of more than 40 genes were compared between susceptible and resistant axenic amastigotes using customized DNA microarrays. The expression of three genes coding for the ABC transporter MRPA (PGPA), S-adenosylhomocysteine hydrolase, and folylpolyglutamate synthase was found to be consistently increased. The levels of cysteine were found to be increased in the mutant. Transfection of the MRPA gene was shown to confer sodium stibogluconate resistance in intracellular parasites. This MRPA-mediated resistance could be reverted by using the glutathione biosynthesis-specific inhibitor buthionine sulfoximine. These results highlight for the first time the role of MRPA in antimony resistance in the amastigote stage of the parasite and suggest a strategy for reversing resistance.