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We have previously shown that resistance can be suppressed with a population biology trap: by identifying situations where resistance to one compound confers hypersensitivity to another (collateral sensitivity), we can design combination therapies that not only kill the parasite but also guide its evolution away from resistance. We applied this concept to the Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme, a well validated antimalarial target with inhibitors in the development pipeline. Here, we report a high-throughput screen to identify compounds specifically active against PfDHODH resistant mutants. We additionally perform extensive cross-resistance profiling allowing us to identify compound pairs demonstrating the potential for mutually incompatible resistance. These combinations represent promising starting points for exploiting collateral sensitivity to extend the useful lifespan of new antimalarial therapeutics.<\/jats:p>","DOI":"10.1021\/acsinfecdis.7b00217","type":"journal-article","created":{"date-parts":[[2018,1,16]],"date-time":"2018-01-16T11:21:52Z","timestamp":1516101712000},"page":"508-515","source":"Crossref","is-referenced-by-count":19,"title":["Identification of\nCollateral Sensitivity to Dihydroorotate Dehydrogenase Inhibitors\nin\n                    <i>Plasmodium falciparum<\/i>"],"prefix":"10.1021","volume":"4","author":[{"given":"Leila Saxby","family":"Ross","sequence":"first","affiliation":[{"name":"Harvard T. H. Chan School of Public Health , , 665 Huntington Avenue , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jose\u0301","family":"Lafuente-Monasterio","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline , , , , ,","place":["Tres Cantos, Madrid, Spain, 28760"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyo","family":"Sakata-Kato","sequence":"additional","affiliation":[{"name":"Harvard T. H. Chan School of Public Health , , 665 Huntington Avenue , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E. K.","family":"Mandt","sequence":"additional","affiliation":[{"name":"Harvard T. H. Chan School of Public Health , , 665 Huntington Avenue , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Gamo","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline , , , , ,","place":["Tres Cantos, Madrid, Spain, 28760"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dyann F.","family":"Wirth","sequence":"additional","affiliation":[{"name":"Harvard T. H. Chan School of Public Health , , 665 Huntington Avenue , , ,","place":["Boston, Massachusetts, United States, 02115"]},{"name":"The Broad Institute , , 415 Main Street , , ,","place":["Cambridge, Massachusetts, United States, 02142"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9560-7643","authenticated-orcid":true,"given":"Amanda K.","family":"Lukens","sequence":"additional","affiliation":[{"name":"Harvard T. H. Chan School of Public Health , , 665 Huntington Avenue , , ,","place":["Boston, Massachusetts, United States, 02115"]},{"name":"The Broad Institute , , 415 Main Street , , ,","place":["Cambridge, Massachusetts, United States, 02142"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,1,16]]},"reference":[{"key":"2026090313162529300_cit1","doi-asserted-by":"crossref","DOI":"10.30875\/4348b814-en","volume-title":"World Malaria Report 2016","author":"World Health Organization.","year":"2016"},{"key":"2026090313162529300_cit2","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/S1473-3099(02)00239-6","article-title":"Epidemiology of drug-resistant malaria","volume":"2","author":"Wongsrichanalai","year":"2002","journal-title":"Lancet Infect. 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A."},{"key":"2026090313162529300_cit6","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.1056\/NEJMc0805011","article-title":"and Artemisinin\nResistance in Cambodia 1 Study, C. Evidence of artemisinin-resistant\nmalaria in western Cambodia","volume":"359","author":"Noedl","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"2026090313162529300_cit7","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1016\/S1473-3099(12)70226-8","article-title":"Resistance to artemisinin-based combination\ntherapy","volume":"12","author":"Breman","year":"2012","journal-title":"Lancet Infect. Dis."},{"key":"2026090313162529300_cit8","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1093\/infdis\/jit415","article-title":"Ordered accumulation\nof mutations conferring resistance to sulfadoxine-pyrimethamine in\nthe Plasmodium falciparum parasite","volume":"209","author":"Mita","year":"2014","journal-title":"J. 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Rep."},{"key":"2026090313162529300_cit23","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1128\/AAC.02110-15","article-title":"Discovery\nof Dual-Stage Malaria Inhibitors with New Targets","volume":"60","author":"Raphemot","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090313162529300_cit24","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1021\/acsinfecdis.6b00101","article-title":"A Novel Methodology\nfor Bioenergetic Analysis of Plasmodium falciparum Reveals a Glucose-Regulated\nMetabolic Shift and Enables Mode of Action Analyses of Mitochondrial\nInhibitors","volume":"2","author":"Sakata-Kato","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"2026090313162529300_cit25","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1016\/0006-2952(92)90213-3","article-title":"Site of action of the\nantimalarial hydroxynaphthoquinone, 2-[trans-4-(4\u2032-chlorophenyl)\ncyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80)","volume":"43","author":"Fry","year":"1992","journal-title":"Biochem. Pharmacol."},{"key":"2026090313162529300_cit26","doi-asserted-by":"publisher","first-page":"3649","DOI":"10.1021\/jm8001026","article-title":"Triazolopyrimidine-based\ndihydroorotate dehydrogenase inhibitors with potent and selective\nactivity against the malaria parasite Plasmodium falciparum","volume":"51","author":"Phillips","year":"2008","journal-title":"J. Med. Chem."},{"key":"2026090313162529300_cit27","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1126\/science.781840","article-title":"Human malaria parasites in continuous culture","volume":"193","author":"Trager","year":"1976","journal-title":"Science"},{"key":"2026090313162529300_cit28","doi-asserted-by":"publisher","first-page":"418","DOI":"10.2307\/3280287","article-title":"Synchronization of Plasmodium falciparum erythrocytic\nstages in culture","volume":"65","author":"Lambros","year":"1979","journal-title":"J. Parasitol."},{"key":"2026090313162529300_cit29","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1016\/j.chembiol.2011.09.016","article-title":"Identification\nand validation of tetracyclic benzothiazepines as Plasmodium falciparum\ncytochrome bc1 inhibitors","volume":"18","author":"Dong","year":"2011","journal-title":"Chem. Biol."},{"key":"2026090313162529300_cit30","doi-asserted-by":"crossref","first-page":"374","DOI":"10.2144\/03342mt01","article-title":"TM4: a free, open-source system for\nmicroarray data management and analysis","volume":"34","author":"Saeed","year":"2003","journal-title":"Biotechniques"},{"key":"2026090313162529300_cit31","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1107\/S0907444911007281","article-title":"Presenting your structures: the CCP4mg\nmolecular-graphics software","volume":"67","author":"McNicholas","year":"2011","journal-title":"Acta Crystallogr.,\nSect. D: Biol. Crystallogr."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.7b00217","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/4\/4\/508\/67303363\/acsinfecdis.7b00217.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/4\/4\/508\/67303363\/acsinfecdis.7b00217.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:16:33Z","timestamp":1788455793000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/4\/4\/508\/845364\/Identification-of-Collateral-Sensitivity-to"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,16]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,1,16]]},"published-print":{"date-parts":[[2018,4,13]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.7b00217","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,16]]}}}