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

Annie N. Cowell, Eva S. Istvan, Amanda K. Lukens, Maria G. Gomez-Lorenzo, Manu Vanaerschot, Tomoyo Sakata-Kato, Erika L. Flannery, Pamela Magistrado, Edward Owen, Matthew Abraham, Gregory La Monte, Heather J. Painter, Roy M. Williams, Virginia Franco, Maria Linares, Ignacio Arriaga, Selina Bopp, Victoria C. Corey, Nina F. Gnädig, Olivia Coburn-FlynnChristin Reimer, Purva Gupta, James M. Murithi, Pedro A. Moura, Olivia Fuchs, Erika Sasaki, Sang W. Kim, Christine H. Teng, Lawrence T. Wang, Asl Akidil, Sophie Adjalley, Paul A. Willis, Dionicio Siegel, Olga Tanaseichuk, Yang Zhong, Yingyao Zhou, Manuel Llinás, Sabine Ottilie, Francisco Javier Gamo, Marcus C.S. Lee, Daniel E. Goldberg, David A. Fidock, Dyann F. Wirth, Elizabeth A. Winzeler

Research output: Contribution to journalArticle

63 Scopus citations

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 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, farnesytransferase 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.

Original languageEnglish
Pages (from-to)191-199
Number of pages9
JournalScience
Volume359
Issue number6372
DOIs
StatePublished - Jan 12 2018

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    Cowell, A. N., Istvan, E. S., Lukens, A. K., Gomez-Lorenzo, M. G., Vanaerschot, M., Sakata-Kato, T., Flannery, E. L., Magistrado, P., Owen, E., Abraham, M., La Monte, G., Painter, H. J., Williams, R. M., Franco, V., Linares, M., Arriaga, I., Bopp, S., Corey, V. C., Gnädig, N. F., ... Winzeler, E. A. (2018). Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science, 359(6372), 191-199. https://doi.org/10.1126/science.aan4472