Wiedemar Natalie, Graf Fabrice E, Zwyer Michaela, Ndomba Emiliana, Kunz Renggli Christina, Cal Monica, Schmidt Remo S, Wenzler Tanja, Mäser Pascal
Swiss Tropical and Public Health Institute, Basel CH-4002, Switzerland.
University of Basel, Basel CH-4001, Switzerland.
Mol Microbiol. 2018 Jan;107(1):57-67. doi: 10.1111/mmi.13854. Epub 2017 Nov 20.
Suramin is one of the first drugs developed in a medicinal chemistry program (Bayer, 1916), and it is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense. Cellular uptake of suramin occurs by endocytosis, and reverse genetic studies with T. b. brucei have linked downregulation of the endocytic pathway to suramin resistance. Here we show that forward selection for suramin resistance in T. brucei spp. cultures is fast, highly reproducible and linked to antigenic variation. Bloodstream-form trypanosomes are covered by a dense coat of variant surface glycoprotein (VSG), which protects them from their mammalian hosts' immune defenses. Each T. brucei genome contains over 2000 different VSG genes, but only one is expressed at a time. An expression switch to one particular VSG, termed VSG , correlated with suramin resistance. Reintroduction of the originally expressed VSG gene in resistant T. brucei restored suramin susceptibility. This is the first report of a link between antigenic variation and drug resistance in African trypanosomes.
苏拉明是药物化学项目中最早研发的药物之一（拜耳公司，1916年），至今仍是由罗德西亚布氏锥虫引起的非洲昏睡病血淋巴期的首选治疗药物。苏拉明通过内吞作用进入细胞，对布氏锥虫的反向遗传学研究表明，内吞途径的下调与苏拉明耐药性有关。在此，我们表明在布氏锥虫属培养物中对苏拉明耐药性进行正向选择快速、高度可重复且与抗原变异有关。血流形式的锥虫被一层致密的变异表面糖蛋白（VSG）所覆盖，这保护它们免受哺乳动物宿主的免疫防御。每个布氏锥虫基因组包含超过2000个不同的VSG基因，但一次仅表达一个。向一种特定的VSG（称为VSG ）的表达转换与苏拉明耐药性相关。在耐药的布氏锥虫中重新引入最初表达的VSG基因可恢复对苏拉明的敏感性。这是关于非洲锥虫抗原变异与耐药性之间联系的首次报道。
