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High-throughput decoding of antitrypanosomal drug efficacy and resistance

机译：高通量解码抗胰岛药物的功效和耐药性

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摘要

The concept of disease-specific chemotherapy was developed a century ago. Dyes and arsenical compounds that displayed selectivity against trypanosomes were central to this work, and the drugs that emerged remain in use for treating human African trypanosomiasis (HAT). The importance of understanding the mechanisms underlying selective drug action and resistance for the development of improved HAT therapies has been recognized, but these mechanisms have remained largely unknown. Here we use all five current HAT drugs for genome-scale RNA interference target sequencing (RIT-seq) screens in Trypanosoma brucei, revealing the transporters, organelles, enzymes and metabolic pathways that function to facilitate antitrypanosomal drug action. RIT-seq profiling identifies both known drug importers and the only known pro-drug activator, and links more than fifty additional genes to drug action. A bloodstream stage-specific invariant surface glycoprotein (ISG75) family mediates suramin uptake, and the API adaptin complex, lysosomal proteases and major lysosomal transmembrane protein, as well as spermidine and N-acetylglucosamine biosynthesis, all contribute to suramin action, further screens link ubiquinone availability to nitro-drug action, plasma membrane P-type H~+-ATPases to pentamidine action, and trypanothione and several putative kinases to melarsoprol action. We also demonstrate a major role for aquaglyceroporins in pentamidine and melarsoprol cross-resistance. These advances in our understanding of mechanisms of antitrypanosomal drug efficacy and resistance will aid the rational design of new therapies and help to combat drug resistance, and provide unprecedented molecular insight into the mode of action of antitrypanosomal drugs.
机译：疾病特异性化学疗法的概念是一个世纪前提出的。对锥虫具有选择性的染料和砷化合物是这项工作的核心，出现的药物仍在治疗人类非洲锥虫病（HAT）中使用。人们已经认识到了解选择性药物作用和耐药性机制对改善HAT疗法发展的重要性，但这些机制在很大程度上仍然未知。在这里，我们将所有五个当前的HAT药物用于布鲁氏锥虫的基因组规模RNA干扰靶标测序（RIT-seq）筛查，揭示了转运蛋白，细胞器，酶和代谢途径，这些功能有助于促进胰锥虫药物的作用。 RIT-seq分析可识别已知的药物进口者和唯一已知的药物前活化剂，并将五十多个其他基因与药物作用相关联。血流阶段特定的不变表面糖蛋白（ISG75）家族介导苏拉明的摄取，API适应蛋白复合物，溶酶体蛋白酶和主要的溶酶体跨膜蛋白，以及亚精胺和N-乙酰氨基葡萄糖的生物合成，都有助于苏拉明的作用，进一步筛选了泛醌可用于硝基药物作用，质膜P型H〜+ -ATP酶可用于喷他action作用，以及锥虫硫酮和几种推定的激酶可用于美拉索尔作用。我们还证明了水甘油糖蛋白在喷他idine和美拉索洛交叉耐药中的主要作用。我们对抗锥虫药功效和耐药机制的理解的这些进步将有助于合理设计新疗法并有助于对抗耐药性，并为抗锥虫药的作用方式提供前所未有的分子洞察力。

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  • 来源
    《Nature》 |2012年第7384期|p.232-236|共5页
  • 作者

    Sam Alsford; Sabine Eckert; Nicola Baker; Lucy Glover; Alejandro Sanchez-Flores; Ka Fai Leung; Daniel J. Turner; Mark C. Field; Matthew Berriman; David Horn;

  • 作者单位

    London School of Hygieneand Tropical Medicine, Keppel Street, London, WC1 E7HT, UK;

    The WellcomeTrustSanger Institute, Hinxton, Cambridge, CB10 1SA, UK,Oxford Nanopore Technologies, 4 Robert Robinson Avenue, Oxford, OX4 4GA, UK;

    London School of Hygieneand Tropical Medicine, Keppel Street, London, WC1 E7HT, UK;

    London School of Hygieneand Tropical Medicine, Keppel Street, London, WC1 E7HT, UK;

    The WellcomeTrustSanger Institute, Hinxton, Cambridge, CB10 1SA, UK;

    Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK;

    The WellcomeTrustSanger Institute, Hinxton, Cambridge, CB10 1SA, UK,Oxford Nanopore Technologies, 4 Robert Robinson Avenue, Oxford, OX4 4GA, UK;

    Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK;

    The WellcomeTrustSanger Institute, Hinxton, Cambridge, CB10 1SA, UK;

    London School of Hygieneand Tropical Medicine, Keppel Street, London, WC1 E7HT, UK;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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