High-throughput decoding of antitrypanosomal drug efficacy and resistance

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, the drugs emerged remain in use for treating human African trypanosomiasis (HAT). importance understanding mechanisms underlying selective drug action resistance development improved HAT therapies has been recognized, but these have remained largely unknown. Here we all five current genome-scale RNA interference target sequencing (RIT-seq) screens Trypanosoma brucei, revealing transporters, organelles, enzymes metabolic pathways function facilitate antitrypanosomal action. RIT-seq profiling identifies both known importers only pro-drug activator, links more than fifty additional genes A bloodstream stage-specific invariant surface glycoprotein (ISG75) family mediates suramin uptake, AP1 adaptin complex, lysosomal proteases major transmembrane protein, as well spermidine N-acetylglucosamine biosynthesis, contribute Further link ubiquinone availability nitro-drug action, plasma membrane P-type H(+)-ATPases pentamidine trypanothione several putative kinases melarsoprol We also demonstrate role aquaglyceroporins cross-resistance. These advances our efficacy will aid rational design new help combat resistance, provide unprecedented molecular insight into mode drugs.