Singh Neeloo
Central Drug Research Institute, Lucknow, India.
Indian J Med Res. 2006 Mar;123(3):411-22.
Leishmania are protozoan parasites distributed worldwide. About 1.5-2.0 million cases are reported in the world annually from this disease and the death toll is estimated to be 57,000. Along with Brazil, Sudan and Bangladesh, India contributes to 90 per cent of the global burden of visceral leishmaniasis (VL). The absence of effective vaccines and vector control programmes, makes chemotherapy the most widely used tool against leishmaniasis. Chemotherapy based on pentavalent antimonials has been used for more than 50 years and remains the mainstay for treatment of leishmaniasis. Clinical resistance to pentavalent antimonials, in the form of sodium antimony gluconate (SAG), has become a major problem in the treatment of kala-azar (visceral leishmaniasis) in India. The mechanism of resistance is unclear in these clinical isolates although a lot of work has been carried out with Leishmania mutants selected in vitro by step-wise increasing drug concentration using the antimony related metal arsenic and more recently sodium antimony gluconate. We for the first time, investigated the molecular aspect of drug resistance in clinically confirmed sodium antimony gluconate resistant field isolates and found that the parasite evaded cytotoxic effects of therapy by enhanced efflux of drugs through overexpressed membrane proteins belonging to the superfamily of ABC (ATP-binding cassette) transporters. Additionally, our study also points towards cell surface changes in resistant isolates.
利什曼原虫是分布于全球的原生动物寄生虫。全球每年报告约150万至200万例该疾病病例，估计死亡人数为57000人。印度与巴西、苏丹和孟加拉国一起，承担了全球内脏利什曼病（VL）90%的负担。由于缺乏有效的疫苗和病媒控制计划，化疗成为治疗利什曼病最广泛使用的手段。基于五价锑的化疗已使用了50多年，仍然是治疗利什曼病的主要方法。在印度，以葡萄糖酸锑钠（SAG）形式出现的对五价锑的临床耐药性已成为治疗黑热病（内脏利什曼病）的一个主要问题。尽管已经对通过逐步增加与锑相关的金属砷以及最近的葡萄糖酸锑钠的药物浓度在体外选择的利什曼原虫突变体进行了大量研究，但这些临床分离株的耐药机制尚不清楚。我们首次研究了临床确诊的葡萄糖酸锑钠耐药现场分离株耐药性的分子方面，发现该寄生虫通过属于ABC（ATP结合盒）转运蛋白超家族的膜蛋白过表达增强药物外排，从而逃避治疗的细胞毒性作用。此外，我们的研究还指出了耐药分离株的细胞表面变化。
