Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance
Drug 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 an...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 2; pp. 799 - 804 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
14.01.2014
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | Drug 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 (CQ ʳ) malaria parasite and with parasites derived by in vitro selection with Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. We screened a chemical library against CQ ˢ and CQ ʳ lines and discovered a drug-like compound (IDI-3783) that was potent only in the CQ ʳ 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. |
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Bibliography: | http://dx.doi.org/10.1073/pnas.1320886110 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributed by Daniel L. Hartl, November 6, 2013 (sent for review October 2, 2013) Author contributions: A.K.L., L.S.R., R.H., F.J.G., M.J.L.-M., M.L.B., D.L.H., R.C.W., and D.F.W. designed research; A.K.L., L.S.R., R.H., F.J.G., M.J.L.-M., and M.L.B. performed research; A.K.L., L.S.R., R.H., R.C.W., and D.F.W. analyzed data; and A.K.L., L.S.R., R.C.W., and D.F.W. wrote the paper. 1A.K.L. and L.S.R. contributed equally to the work. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1320886110 |