Seifert Karin, Pérez-Victoria F Javier, Stettler Marianne, Sánchez-Cañete María P, Castanys Santiago, Gamarro Francisco, Croft Simon L
Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Int J Antimicrob Agents. 2007 Sep;30(3):229-35. doi: 10.1016/j.ijantimicag.2007.05.007. Epub 2007 Jul 12.
Miltefosine (hexadecylphosphocholine) is the first oral antileishmanial drug. In this study, we addressed the question whether miltefosine-resistant Leishmania donovani promastigotes transform to miltefosine-resistant amastigotes. A promastigote line, M-mutR, showed defective internalisation of miltefosine owing to mutations in LdMT, similar to previously described resistant lines. M-mutR parasites were infective to macrophages in vitro as well as in BALB/c mice in vivo. There was good correlation of in vitro resistance indices between promastigotes and intracellular amastigotes. Most importantly, M-mutR parasites retained the resistant phenotype in vivo, with no decrease of hepatic burden in BALB/c mice following miltefosine treatment up to 30 mg/kg (ca. 90% inhibition in wild-type infections). No cross-resistance to other antileishmanial drugs was observed in M-mutR amastigotes.
米替福新（十六烷基磷酸胆碱）是第一种口服抗利什曼原虫药物。在本研究中，我们探讨了对米替福新耐药的杜氏利什曼原虫前鞭毛体是否会转变为对米替福新耐药的无鞭毛体这一问题。一个前鞭毛体株系M-mutR，由于利什曼原虫膜转运蛋白（LdMT）发生突变，导致米替福新的内化存在缺陷，这与先前描述的耐药株系类似。M-mutR寄生虫在体外对巨噬细胞具有感染性，在体内对BALB/c小鼠也具有感染性。前鞭毛体和细胞内无鞭毛体之间的体外耐药指数具有良好的相关性。最重要的是，M-mutR寄生虫在体内保留了耐药表型，在米替福新以高达30 mg/kg的剂量治疗后，BALB/c小鼠的肝脏负担没有减轻（在野生型感染中约有90%的抑制率）。在M-mutR无鞭毛体中未观察到对其他抗利什曼原虫药物的交叉耐药性。
