Cowell Annie N, Istvan Eva S, Lukens Amanda K, Gomez-Lorenzo Maria G, Vanaerschot Manu, Sakata-Kato Tomoyo, Flannery Erika L, Magistrado Pamela, Owen Edward, Abraham Matthew, LaMonte Gregory, Painter Heather J, Williams Roy M, Franco Virginia, Linares Maria, Arriaga Ignacio, Bopp Selina, Corey Victoria C, Gnädig Nina F, Coburn-Flynn Olivia, Reimer Christin, Gupta Purva, Murithi James M, Moura Pedro A, Fuchs Olivia, Sasaki Erika, Kim Sang W, Teng Christine H, Wang Lawrence T, Akidil Aslı, Adjalley Sophie, Willis Paul A, Siegel Dionicio, Tanaseichuk Olga, Zhong Yang, Zhou Yingyao, Llinás Manuel, Ottilie Sabine, Gamo Francisco-Javier, Lee Marcus C S, Goldberg Daniel E, Fidock David A, Wirth Dyann F, Winzeler Elizabeth A
School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093, USA.
Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science. 2018 Jan 12;359(6372):191-199. doi: 10.1126/science.aan4472.
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 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 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.
通过体外进化结合全基因组分析进行化学遗传学特征分析，可以识别抗疟药物靶点和耐药基因。我们对262种对37种不同化合物耐药的寄生虫进行了基因组分析。我们发现与耐药性获得相关的83个基因中有159个基因扩增和148个非同义变化，其中基因扩增占耐药性获得事件的三分之一。除了证实先前确定的多药耐药机制外，我们还发现了迄今未被认识的药物靶点-抑制剂对，包括胸苷酸合成酶和苯并喹唑啉酮、法尼基转移酶和嘧啶二酮，以及二肽基肽酶和芳基脲。对耐药基因组和可成药基因组的这种探索可能会指导药物发现和结构生物学研究，同时也会增进我们对疟原虫可用耐药机制的理解。
