3 years ago

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

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

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.

Publisher URL: http://science.sciencemag.org/cgi/content/short/359/6372/191

DOI: 10.1126/science.aan4472

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