Increased expression of ABC transport proteins is associated with ivermectin resistance in the model nematode Caenorhabditis elegans
Increased expression of ABC transport proteins is associated with ivermectin resistance in the model nematode Caenorhabditis elegans
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DOI：
10.1016/j.ijpara.2008.06.009
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发表时间：
2009-01-15
影响因子：
4
通讯作者：
Davey, Mary W.
中科院分区：
文献类型：
--
作者：
James, Catherine E.;Davey, Mary W.
对化学治疗剂的广泛耐药性是人类健康和农业面临的最大挑战之一，目前已记录到对所有现有驱虫剂的耐药性，并且几乎没有新的药剂或疫苗可用。了解寄生线虫耐药性的发展对于延长当前驱虫剂的效力、开发用于监测耐药性的标记物以及设计新的化疗剂或靶向物是至关重要的。本研究描述了通过逐步暴露于增加剂量的伊维菌素（从1 ng/ml的无毒剂量开始），开发模型线虫秀丽隐杆线虫的伊维菌素耐药菌株。开发的耐药菌株显示出多药耐药表型，对相关药物莫昔克丁和其他驱虫药左旋咪唑和噻嘧啶具有交叉耐药性，但对阿苯达唑无交叉耐药性。耐药与多药耐药蛋白（MRPs）和P-糖蛋白的表达增加有关。对伊维菌素的耐药性是可逆的MRP，P-糖蛋白和谷胱甘肽生物合成抑制剂的共同管理，确认这些蛋白质的参与耐药性。在我们的模型中，对低水平伊维菌素（
Widespread resistance to chemotherapeutic agents is one of the biggest challenges facing human health and the agricultural industry, with resistance to all current anthelmintics now recorded and few new agents or vaccines available. Understanding the development of drug resistance in parasitic nematodes is critical to prolonging the efficacy of current anthelmintics, developing markers for monitoring drug resistance and is beneficial in the design of new chemotherapeutic agents or tat-gets. This study describes the development of ivermectin-resistant strains of the model nematode Caenorhabditis elegans through step-wise exposure to increasing doses of ivermectin commencing with a non-toxic dose of I ng/ml. Resistant strains were developed that displayed a multidrug resistance phenotype with cross-resistance to the related drug moxidectin and to other anthelmintics, levamisole and pyrantel, but not albendazole. Resistance was associated with increased expression of the multidrug resistance proteins (MRPs) and P-glycoproteins. Resistance to ivermectin was reversible by the co-administration of MRP, P-glycoprotein and glutathione biosynthesis inhibitors, confirming the involvement of these proteins in resistance. In our model, resistance to low levels of ivermectin (