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

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Journal:
Science (New York, N.Y.), Volume: 359, Issue: 6372
Published:
January 12, 2018
PMID:
29326268
Authors:
Annie N Cowell AN, Eva S Istvan ES, Amanda K Lukens AK, Maria G Gomez-Lorenzo MG, Manu Vanaerschot M, Tomoyo Sakata-Kato T, Erika L Flannery EL, Pamela Magistrado P, Edward Owen E, Matthew Abraham M, Gregory LaMonte G, Heather J Painter HJ, Roy M Williams RM, Virginia Franco V, Maria Linares M, Ignacio Arriaga I, Selina Bopp S, Victoria C Corey VC, Nina F Gnädig NF, Olivia Coburn-Flynn O, Christin Reimer C, Purva Gupta P, James M Murithi JM, Pedro A Moura PA, Olivia Fuchs O, Erika Sasaki E, Sang W Kim SW, Christine H Teng CH, Lawrence T Wang LT, Aslı Akidil A, Sophie Adjalley S, Paul A Willis PA, Dionicio Siegel D, Olga Tanaseichuk O, Yang Zhong Y, Yingyao Zhou Y, Manuel Llinás M, Sabine Ottilie S, Francisco-Javier Gamo FJ, Marcus C S Lee MCS, Daniel E Goldberg DE, David A Fidock DA, Dyann F Wirth DF, Elizabeth A Winzeler EA
Abstract:

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.