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Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics

Cowell, Annie and LaMonte, Greeg and Abraham, Matthew and Flannery, Erika and William, Roy and Sasaki, Erica and Corey, Victoria and Lukens, Amanda and Istvan, Eva and Lee, Marcus and Franco, Virginia and Reimer, Christin and Magistrado, Pamela and Coburn-Flynn, Olivia and Sakata-Kato, Tomoyo and Bopp, Selina and Gupta, Purva and Fuchs, Olivia and Kim, Sang and Teng, Christine and Gnadig, Nina and Vanaerschot, Manu and Murithi, James and Linares, Maria and Cozar, Cristina and Gomez-Lorenzo, Maria and Prats, Sara and Arriaga, Ignacio and Wang, Lawrence and Ottilie, Sabine and Siegel, Dionicio and Tanaseichuk, Olga and Zhong, Yang and Zhou, Yingyao and Willis, Paul and Gamo, Francisco-Javier and Goldberg, Daniel and Fidock, David and Wirth, Dyann and Winzeler, Elizabeth (2017) Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics. Science.

Abstract

Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify novel antimalarial drug targets and drug resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. This study reveals 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with resistance acquisition where gene amplifications contribute to 1/3 of drug resistance acquisition events. Beyond confirming previously identified multidrug resistance mechanisms we find new 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 drug-able genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

Item Type: Article
Keywords: multidrugresistance, malaria, evolution, genome, sequencing
Date Deposited: 18 Nov 2017 00:45
Last Modified: 18 Nov 2017 00:45
URI: https://oak.novartis.com/id/eprint/32600

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