Publication:
Mapping the malaria parasite drug-able genome using<i>in vitro</i>evolution and chemogenomics

Loading...
Thumbnail Image
Full text at PDC
Publication Date
2018-01-12
Advisors (or tutors)
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
American Association for the Advancement of Science
Citations
Google Scholar
Research Projects
Organizational Units
Journal Issue
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, 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.
Description
Keywords
Citation
Collections