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Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.

Annie N CowellEva S IstvanAmanda K LukensMaria G Gomez-LorenzoManu VanaerschotTomoyo Sakata-KatoErika L FlanneryPamela MagistradoEdward OwenMatthew AbrahamGregory LaMonteHeather J PainterRoy M WilliamsVirginia FrancoMaría LinaresIgnacio ArriagaSelina BoppVictoria C CoreyNina F GnädigOlivia Coburn-FlynnChristin ReimerPurva GuptaJames M MurithiPedro A MouraOlivia FuchsErika SasakiSang W KimChristine H TengLawrence T WangAslı AkidilSophie AdjalleyPaul A WillisDionicio SiegelOlga TanaseichukYang ZhongYingyao ZhouManuel LlinásSabine OttilieFrancisco-Javier GamoMarcus Chee San LeeDaniel E GoldbergDavid A FidockDyann F WirthElizabeth A Winzeler
Published in: Science (New York, N.Y.) (2018)
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.
Keyphrases
  • plasmodium falciparum
  • genome wide
  • drug discovery
  • genome wide identification
  • dna methylation
  • copy number
  • high resolution
  • genome wide analysis
  • emergency department
  • quality improvement
  • mass spectrometry