Dissecting Plasmodium drug resistance Malaria is a deadly disease with no effective vaccine. Physicians thus depend on antimalarial drugs to save lives, but such compounds are often rendered ineffective when parasites evolve resistance. Cowell et al. systematically studied patterns of Plasmodium falciparum genome evolution by analyzing the sequences of clones that were resistant to diverse antimalarial compounds across the P. falciparum life cycle (see the Perspective by Carlton). The findings identify hitherto unrecognized drug targets and drug-resistance genes, as well as additional alleles in known drug-resistance genes. Science, this issue p. 191; see also p. 159 Genome sequencing elucidates potential drug resistance in the malaria parasite and identifies antimalarial targets. Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

中文翻译：

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使用体外进化和化学基因组学绘制疟原虫可药物基因组图

剖析疟原虫耐药性 疟疾是一种致命疾病，尚无有效疫苗。因此，医生依靠抗疟药来挽救生命，但当寄生虫产生抗药性时，此类化合物往往无效。考威尔等人。通过分析在整个恶性疟原虫生命周期中对多种抗疟化合物具有抗性的克隆序列，系统地研究了恶性疟原虫基因组进化的模式（参见 Carlton 的观点）。这些发现确定了迄今为止未被识别的药物靶点和耐药基因，以及已知耐药基因中的其他等位基因。科学，这个问题 p。191; 另见第。159 基因组测序阐明了疟原虫的潜在耐药性并确定了抗疟靶点。通过体外进化结合全基因组分析的化学遗传学表征可以识别抗疟药物靶点和耐药基因。我们对 262 种对 37 种不同化合物具有抗性的恶性疟原虫进行了基因组分析。我们在与耐药性获得相关的 83 个基因中发现了 159 个基因扩增和 148 个非同义变化，其中基因扩增导致了三分之一的耐药性获得事件。除了证实先前确定的多药耐药机制外，我们还发现了迄今为止尚未识别的药物靶标-抑制剂对，包括胸苷酸合酶和苯并喹唑啉酮、法呢基转移酶和嘧啶二酮，以及二肽基肽酶和芳基脲。对 P 的这种探索。