Overcoming multidrug-resistance in hookworms

项目摘要 犬钩虫引起皮肤幼虫游走和嗜酸性肠炎 人类。这些人类疾病无法根除的原因是 寄生虫在犬类宿主体内持续存在。犬嗜血杆菌多药耐药株的研究 现在正在美国流传。此外，特定的生命周期阶段(组织- 栖息的幼虫)对驱虫剂耐受，即使该分离物被认为是“药物” 易受影响的。“ 我们的假设是，犬艾美耳球虫通过渗透性逃避药物治疗。 将驱虫药排出并阻止其结合的糖蛋白(P-糖蛋白) 靶标受体。在本申请中，我们建议1)识别光谱 P-糖蛋白抑制增强的驱虫药，2)记录 对每一类药物反应的Pgp表达谱，3)绘制精确的组织图 在表达PGP的情况下，4)表征ACA-PGP-11的药理特性， 和5)经验性地确定线虫P-糖蛋白的特定部位的区域 可能会被利用。我们的结果将为未来的研究提供信息，以检验这一假设 线虫特异性P-糖蛋白抑制剂可用于恢复多发性硬化症的疗效 现有的驱虫药和克服抗药性的钩虫。

Project Summary Ancylostoma caninum causes cutaneous larva migrans and eosinophilic enteritis in humans. The reason these human diseases cannot be eliminated is because the parasite persists in the canine reservoir host. Multi-drug resistant isolates of A. caninum are now circulating in the United States. In addition, specific life cycle stages (tissue- dwelling larvae) are tolerant of anthelmintics even when the isolate is considered “drug susceptible.” Our hypothesis is that A. caninum evades drug treatment with permeability glycoproteins (P-glycoproteins) that efflux anthelmintics and prevent them from binding target receptors. In this application we propose to 1) identify the spectrum of anthelmintics enhanced by P-glycoprotein inhibition in A. caninum, 2) record the repertoire of Pgps expressed in response to each drug class, 3) map the precise tissues where Pgps are expressed, 4) characterize the pharmacological profile of Aca-Pgp-11, and 5) empirically determine regions of specific sites of nematode P-glycoprotein that could be exploited. Our results will inform future studies testing the hypothesis that nematode-specific P-glycoprotein inhibitors can be used to restore efficacy of multiple existing anthelmintics and overcome drug resistant Ancylostoma.