Laffitte Marie-Claude N, Leprohon Philippe, Légaré Danielle, Ouellette Marc
Centre de Recherche en Infectiologie, CRCHU de Québec, 2705 Boul. Laurier, Québec, Qc, G1V 4G2, Canada.
Parasitol Res. 2016 Oct;115(10):3699-703. doi: 10.1007/s00436-016-5195-y. Epub 2016 Jul 26.
Miltefosine is the first oral drug used in chemotherapy against leishmaniasis. In vitro studies found that resistance to miltefosine in Leishmania is often associated with the acquisition of point mutations in the miltefosine transporter, leading to a decrease in drug uptake. In this study, the dynamics of mutations upon miltefosine selection was studied by deep-sequencing of the miltefosine transporter gene. Deep-sequencing data revealed that no mutation was detected in the miltefosine transporter at sub-inhibitory concentrations of miltefosine. We show that the prevalence of mutated alleles was increasing when the drug pressure heightened, that more mutations were observed in highly resistant mutants, and that most mutations remained when parasites were cultured for a few passages in the absence of miltefosine.
米替福新是第一种用于治疗利什曼病的口服化疗药物。体外研究发现，利什曼原虫对米替福新的耐药性通常与米替福新转运蛋白发生点突变有关，从而导致药物摄取减少。在本研究中，通过对米替福新转运蛋白基因进行深度测序，研究了米替福新选择作用下突变的动态变化。深度测序数据显示，在亚抑制浓度的米替福新作用下，米替福新转运蛋白未检测到突变。我们发现，当药物压力增加时，突变等位基因的流行率上升，在高抗性突变体中观察到更多突变，并且当寄生虫在无米替福新的情况下传代培养几代后，大多数突变仍然存在。
