{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:43:01Z","timestamp":1766486581403,"version":"3.41.2"},"reference-count":28,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | NIH | OSC | Common Fund","award":["R01AI139179"],"award-info":[{"award-number":["R01AI139179"]}]},{"name":"HHS | NIH | OSC | Common Fund","award":["R01AI075045"],"award-info":[{"award-number":["R01AI075045"]}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"crossref","award":["RD\/15\/0001"],"award-info":[{"award-number":["RD\/15\/0001"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"crossref","award":["RD\/15\/0001"],"award-info":[{"award-number":["RD\/15\/0001"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,9,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Novel antimalarials are urgently needed to combat rising resistance to available drugs. The imidazolopiperazine ganaplacide is a promising drug candidate, but decreased susceptibility of laboratory strains has been linked to polymorphisms in the\n              <jats:italic>Plasmodium falciparum<\/jats:italic>\n              cyclic amine resistance locus (PfCARL), acetyl-CoA transporter (PfACT), and UDP-galactose transporter (PfUGT). To characterize parasites causing disease in Africa, we assessed\n              <jats:italic>ex vivo<\/jats:italic>\n              drug susceptibilities to ganaplacide in 750\n              <jats:italic>P<\/jats:italic>\n              .\n              <jats:italic>falciparum<\/jats:italic>\n              isolates collected in Uganda from 2017 to 2023. Drug susceptibilities were assessed using a 72-hour SYBR Green growth inhibition assay. The median IC\n              <jats:sub>50<\/jats:sub>\n              for ganaplacide was 13.8 nM, but some isolates had up to 31-fold higher IC\n              <jats:sub>50<\/jats:sub>\n              s (31\/750 with IC\n              <jats:sub>50<\/jats:sub>\n              &gt; 100 nM). To assess genotype-phenotype associations, we sequenced genes potentially mediating altered ganaplacide susceptibility in the isolates using molecular inversion probe and dideoxy sequencing methods. PfCARL was highly polymorphic, with eight mutations present in &gt;5% of isolates. None of these eight mutations had previously been selected in laboratory strains with\n              <jats:italic>in vitro<\/jats:italic>\n              drug pressure and none were found to be significantly associated with decreased ganaplacide susceptibility. Mutations in PfACT and PfUGT were found in \u22645% of isolates, except for two frequent (&gt;20%) mutations in PfACT; one mutation in PfACT (I140V) was associated with a modest decrease in susceptibility. Overall, Ugandan\n              <jats:italic>P. falciparum<\/jats:italic>\n              isolates were mostly highly susceptible to ganaplacide. Known resistance mediators were polymorphic, but mutations previously selected with\n              <jats:italic>in vitro<\/jats:italic>\n              drug pressure were not seen, and mutations identified in the Ugandan isolates were generally not associated with decreased ganaplacide susceptibility.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.00466-24","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T13:02:24Z","timestamp":1723554144000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["<i>Ex vivo<\/i>\n            susceptibilities to ganaplacide and diversity in potential resistance mediators in Ugandan\n            <i>Plasmodium falciparum<\/i>\n            isolates"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2026-345X","authenticated-orcid":true,"given":"Oriana","family":"Kreutzfeld","sequence":"first","affiliation":[{"name":"University of California, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Orena","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Okitwi","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick K.","family":"Tumwebaze","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oswald","family":"Byaruhanga","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Katairo","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9984-8030","authenticated-orcid":true,"given":"Melissa D.","family":"Conrad","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Legac","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shreeya","family":"Garg","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Crudale","sequence":"additional","affiliation":[{"name":"Brown University, Providence, Rhode Island, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ozkan","family":"Aydemir","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Giesbrecht","sequence":"additional","affiliation":[{"name":"Brown University, Providence, Rhode Island, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel L.","family":"Nsobya","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration, Kampala, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Blasco","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Geneva, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maelle","family":"Duffey","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Geneva, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Rouillier","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Geneva, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey A.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Brown University, Providence, Rhode Island, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8437-9382","authenticated-orcid":true,"given":"Roland A.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Dominican University of California, San Rafael, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7953-7622","authenticated-orcid":true,"given":"Philip J.","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"University of California, San Francisco, California, 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