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DOI | 10.1126/science.aan4472 |
Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics | |
Cowell, Annie N.1; Istvan, Eva S.2,3; Lukens, Amanda K.4,5; Gomez-Lorenzo, Maria G.6; Vanaerschot, Manu7; Sakata-Kato, Tomoyo4; Flannery, Erika L.1; Magistrado, Pamela4; Owen, Edward8; Abraham, Matthew1; LaMonte, Gregory1; Painter, Heather J.8; Williams, Roy M.1; Franco, Virginia6; Linares, Maria6; Arriaga, Ignacio6; Bopp, Selina4; Corey, Victoria C.1; Gnadig, Nina F.7; Coburn-Flynn, Olivia7; Reimer, Christin1; Gupta, Purva1; Murithi, James M.7; Moura, Pedro A.7; Fuchs, Olivia1; Sasaki, Erika1; Kim, Sang W.1; Teng, Christine H.1; Wang, Lawrence T.1; Akidil, Asli9; Adjalley, Sophie9; Willis, Paul A.10; Siegel, Dionicio11; Tanaseichuk, Olga12; Zhong, Yang12; Zhou, Yingyao12; Llinas, Manuel8; Ottilie, Sabine1; Gamo, Francisco-Javier6; Lee, Marcus C. S.7,9; Goldberg, Daniel E.2,3; Fidock, David A.7,13; Wirth, Dyann F.4,5; Winzeler, Elizabeth A.1,11 | |
2018-01-12 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2018 |
卷号 | 359期号:6372页码:191-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Spain; England; Switzerland |
英文摘要 | 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000419816600041 |
WOS关键词 | PLASMODIUM-FALCIPARUM MALARIA ; MULTIDRUG-RESISTANCE ; ANTIMALARIAL-DRUG ; CLINICAL CANDIDATE ; LIFE-CYCLE ; TRANSPORTER ; REVEALS ; BINDING ; PROTEIN ; GENE |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/197756 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Univ Calif San Diego, Sch Med, 9500 Gilman Dr, La Jolla, CA 92093 USA; 2.Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA; 3.Washington Univ, Sch Med, Dept Mol Biol, St Louis, MO 63110 USA; 4.Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA; 5.Broad Inst, Infect Dis Program, 415 Main St, Cambridge, MA 02142 USA; 6.GlaxoSmithKline, Malaria Discovery Performance Unit, Tres Cantos Med Dev Campus,Severo Ochoa 2, Madrid 28760, Spain; 7.Columbia Univ Coll Phys & Surg, Dept Microbiol & Immunol, 630 W 168th St, New York, NY 10032 USA; 8.Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA; 9.Wellcome Sanger Inst, Malaria Programme, Wellcome Genome Campus, Hinxton CB10 1SA, Cambs, England; 10.Med Malaria Venture, POB 1826,20 Route Prebois, CH-1215 Geneva 15, Switzerland; 11.UCSD, Skaggs Sch Pharm & Pharmaceut Sci, 9500 Gilman Dr, La Jolla, CA 92093 USA; 12.Novartis Res Fdn, Genom Inst, 10675 John J Hopkins Dr, San Diego, CA 92121 USA; 13.Columbia Univ Coll Phys & Surg, Div Infect Dis, 630 W 168th St, New York, NY 10032 USA |
推荐引用方式 GB/T 7714 | Cowell, Annie N.,Istvan, Eva S.,Lukens, Amanda K.,et al. Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics[J]. SCIENCE,2018,359(6372):191-+. |
APA | Cowell, Annie N..,Istvan, Eva S..,Lukens, Amanda K..,Gomez-Lorenzo, Maria G..,Vanaerschot, Manu.,...&Winzeler, Elizabeth A..(2018).Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.SCIENCE,359(6372),191-+. |
MLA | Cowell, Annie N.,et al."Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics".SCIENCE 359.6372(2018):191-+. |
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