{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:01:45Z","timestamp":1790704905143,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI139179"],"award-info":[{"award-number":["R01AI139179"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI075045"],"award-info":[{"award-number":["R01AI075045"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"publisher","award":["RD\/15\/0001"],"award-info":[{"award-number":["RD\/15\/0001"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug-susceptibility data for P falciparum field isolates are limited.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We studied ex vivo PfDHFR inhibitor susceptibilities of 559 isolates from Tororo and Busia districts, Uganda, from 2016 to 2020, sequenced 383 isolates, and assessed associations between genotypes and drug-susceptibility phenotypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Median half-maximal inhibitory concentrations (IC50s) were 42 100 nM for pyrimethamine, 1200 nM for cycloguanil, 13000 nM for proguanil, and 0.6 nM for P218. Among sequenced isolates, 3 PfDHFR mutations, 51I (100%), 59R (93.7%), and 108N (100%), were very common, as previously seen in Uganda, and another mutation, 164L (12.8%), had moderate prevalence. Increasing numbers of mutations were associated with decreasing susceptibility to pyrimethamine, cycloguanil, and P218, but not proguanil, which does not act directly against PfDHFR. Differences in P218 susceptibilities were modest, with median IC50s of 1.4 nM for parasites with mixed genotype at position 164 and 5.7 nM for pure quadruple mutant (51I\/59R\/108N\/164L) parasites.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Resistance-mediating PfDHFR mutations were common in Ugandan isolates, but P218 retained excellent activity against mutant parasites.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiab435","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T16:02:23Z","timestamp":1630339343000},"page":"696-704","source":"Crossref","is-referenced-by-count":16,"title":["Decreased Susceptibility to Dihydrofolate Reductase Inhibitors Associated With Genetic Polymorphisms in Ugandan <i>Plasmodium falciparum<\/i> Isolates"],"prefix":"10.1093","volume":"225","author":[{"given":"Oriana","family":"Kreutzfeld","sequence":"first","affiliation":[{"name":"University of California, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick K","family":"Tumwebaze","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oswald","family":"Byaruhanga","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Katairo","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Okitwi","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Orena","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Dominican University of California, San Rafael, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Legac","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa D","family":"Conrad","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam L","family":"Nsobya","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozkan","family":"Aydemir","sequence":"additional","affiliation":[{"name":"Brown University, Providence, Rhode Island, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A","family":"Bailey","sequence":"additional","affiliation":[{"name":"Brown University, Providence, Rhode Island, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maelle","family":"Duffey","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland A","family":"Cooper","sequence":"additional","affiliation":[{"name":"Dominican University of California, San Rafael, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"2022021508043142100_CIT0001","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1073\/pnas.87.8.3018","article-title":"Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria","volume":"87","author":"Peterson","year":"1990","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022021508043142100_CIT0002","volume-title":"WHO Guidelines for malaria","author":"World Health Organization.","year":"2021"},{"key":"2022021508043142100_CIT0003","author":"Centers for Disease Control and Prevention."},{"key":"2022021508043142100_CIT0004","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1124\/pr.57.1.4","article-title":"Mechanisms of resistance of malaria parasites to antifolates","volume":"57","author":"Gregson","year":"2005","journal-title":"Pharmacol 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