{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:41:50Z","timestamp":1781109710845,"version":"3.54.1"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"2","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2014,1,14]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Drug resistance is a major problem in treating malaria infections. Resistance pathways are limited by evolutionary fitness constraints, and these pathways can be anticipated and preemptively blocked. We identified compounds selective for mutant malaria parasites that are resistant to either clinically used (chloroquine) or in-development dihydroorotate dehydrogenase (DHODH) inhibitor therapies. In both cases, resistance selections of mutant parasites with the matching mutant-selective drug led to a reversion to the wild-type phenotype. Additionally, combination selection of wild-type parasites with paired wild-type and mutant-type DHODH inhibitors failed to produce resistant parasites. These findings indicate that pairing inhibitors that target the bulk wild-type population and the small, emerging resistant population can suppress the rise and spread of drug resistance.<\/jats:p>","DOI":"10.1073\/pnas.1320886110","type":"journal-article","created":{"date-parts":[[2013,12,31]],"date-time":"2013-12-31T20:27:21Z","timestamp":1388521641000},"page":"799-804","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":58,"title":["Harnessing evolutionary fitness in\n                    <i>Plasmodium falciparum<\/i>\n                    for drug discovery and suppressing resistance"],"prefix":"10.1073","volume":"111","author":[{"given":"Amanda K.","family":"Lukens","sequence":"first","affiliation":[{"name":"Infectious Disease Initiative, Broad Institute, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila Saxby","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Heidebrecht","sequence":"additional","affiliation":[{"name":"Infectious Disease Initiative, Broad Institute, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Javier Gamo","sequence":"additional","affiliation":[{"name":"Tres Cantos Medicine Development Campus, GlaxoSmithKline, Parque Tecnol\u00f3gico de Madrid, 28760 Tres Cantos, Spain; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J.","family":"Lafuente-Monasterio","sequence":"additional","affiliation":[{"name":"Tres Cantos Medicine Development Campus, GlaxoSmithKline, Parque Tecnol\u00f3gico de Madrid, 28760 Tres Cantos, Spain; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Booker","sequence":"additional","affiliation":[{"name":"Genzyme Corporation, Waltham, MA 02451;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L.","family":"Hartl","sequence":"additional","affiliation":[{"name":"Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger C.","family":"Wiegand","sequence":"additional","affiliation":[{"name":"Infectious Disease Initiative, Broad Institute, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dyann F.","family":"Wirth","sequence":"additional","affiliation":[{"name":"Infectious Disease Initiative, Broad Institute, Cambridge, MA 02142;"},{"name":"Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,12,31]]},"reference":[{"key":"e_1_3_3_1_2","volume-title":"World Malaria Report","author":"World Health Organization","year":"2011","unstructured":"; World Health Organization World Malaria Report (World Health Organization, Geneva, 2011)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808859"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12041-011-0072-z"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkp449"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2004.10.013"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00096-X"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2324"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature00813"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa062032"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3544220"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.38.22393"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1175667"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(88)81111-2"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.285.6343.674"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444905042642"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.162081"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.2174\/187152610791163336"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(05)00077-8"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/ml200143c"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm801343r"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm8001026"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi702218c"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.10.025"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1179123"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn814"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01607-06"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.11.4097-4102.2004"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444911007281"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1320886110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T23:22:04Z","timestamp":1649805724000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1320886110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,31]]},"references-count":30,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2014,1,14]]}},"alternative-id":["10.1073\/pnas.1320886110"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1320886110","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12,31]]},"assertion":[{"value":"2013-12-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}