High-throughput decoding of antitrypanosomal drug efficacy and resistance

Sam Alsford, Sabine Eckert, Nicola Baker, Lucy Glover, Alejandro Sanchez-Flores, Ka Fai Leung, Daniel J. Turner, Mark C. Field, Matthew Berriman, David Horn (Lead / Corresponding author)

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    205 Citations (Scopus)

    Abstract

    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 prodrug 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 AP1 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.

    Original languageEnglish
    Pages (from-to)232-236
    Number of pages6
    JournalNature
    Volume482
    Issue number7384
    DOIs
    Publication statusPublished - 9 Feb 2012

    Keywords

    • LYSOSOME
    • RNAI
    • BLOOD-STREAM FORMS
    • SURAMIN
    • EXPRESSION
    • HUMAN AFRICAN TRYPANOSOMIASIS
    • TRANSPORTER
    • GLYCOPROTEIN
    • DIAMIDINE
    • BRUCEI

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