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

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