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dc.contributor.authorLukens, Amanda Kathleen
dc.contributor.authorRoss, L. S.
dc.contributor.authorHeidebrecht, Richard W
dc.contributor.authorJavier Gamo, F.
dc.contributor.authorLafuente-Monasterio, M. J.
dc.contributor.authorBooker, M. L.
dc.contributor.authorHartl, Daniel L.
dc.contributor.authorWiegand, R. C.
dc.contributor.authorWirth, Dyann F.
dc.date.accessioned2015-10-02T14:41:59Z
dc.date.issued2013
dc.identifier.citationLukens, A. K., L. S. Ross, R. Heidebrecht, F. Javier Gamo, M. J. Lafuente-Monasterio, M. L. Booker, D. L. Hartl, R. C. Wiegand, and D. F. Wirth. 2013. “Harnessing Evolutionary Fitness in Plasmodium Falciparum for Drug Discovery and Suppressing Resistance.” Proceedings of the National Academy of Sciences 111 (2) (December 31): 799–804. doi:10.1073/pnas.1320886110.en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:22898357
dc.description.abstractDrug resistance emerges in an ecological context where fitness costs restrict the diversity of escape pathways. These pathways are targets for drug discovery, and here we demonstrate that we can identify small-molecule inhibitors that differentially target resistant parasites. Combining wild-type and mutant-type inhibitors may prevent the emergence of competitively viable resistance. We tested this hypothesis with a clinically derived chloroquine-resistant (CQr) malaria parasite and with parasites derived by in vitro selection with Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. We screened a chemical library against CQs and CQr lines and discovered a drug-like compound (IDI-3783) that was potent only in the CQr line. Surprisingly, in vitro selection of Plasmodium falciparum resistant to IDI-3783 restored CQ sensitivity, thereby indicating that CQ might once again be useful as a malaria therapy. In parallel experiments, we selected P. falciparum lines resistant to structurally unrelated PfDHODH inhibitors (Genz-666136 and DSM74). Both selections yielded resistant lines with the same point mutation in PfDHODH:E182D. We discovered a compound (IDI-6273) more potent against E182D than wild-type parasites. Selection of the E182D mutant with IDI-6273 yielded a reversion to the wild-type protein sequence and phenotype although the nucleotide sequence was different. Importantly, selection with a combination of Genz-669178, a wild-type PfDHODH inhibitor, and IDI-6273, a mutant-selective PfDHODH inhibitor, did not yield resistant parasites. These two examples demonstrate that the compromise between resistance and evolutionary fitness can be exploited to design therapies that prevent the emergence and spread of resistant organisms.en_US
dc.description.sponsorshipOrganismic and Evolutionary Biologyen_US
dc.language.isoen_USen_US
dc.publisherProceedings of the National Academy of Sciencesen_US
dc.relation.isversionof10.1073/pnas.1320886110en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896170/en_US
dash.licenseLAA
dc.titleHarnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistanceen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dash.depositing.authorHartl, Daniel L.
dc.date.available2015-10-02T14:41:59Z
dc.identifier.doi10.1073/pnas.1320886110*
dash.contributor.affiliatedHeidebrecht, Richard
dash.contributor.affiliatedLukens, Amanda
dash.contributor.affiliatedWirth, Dyann
dash.contributor.affiliatedHartl, Daniel


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