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This study evaluated the in vitro activity of omadacycline against <jats:italic>Plasmodium falciparum<\/jats:italic> and <jats:italic>Plasmodium cynomolgi<\/jats:italic> and its in vivo efficacy against <jats:italic>Plasmodium berghei<\/jats:italic> in experimental malaria models to assess its potential as an antimalarial drug.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Fluorescence-based assays were used to assess the in vitro blood and liver stage activity of omadacycline and doxycycline against <jats:italic>P. falciparum<\/jats:italic> and <jats:italic>P. cynomolgi<\/jats:italic> laboratory clones. In vivo liver and early-stage blood stage efficacy were evaluated in a murine model of <jats:italic>P. berghei<\/jats:italic> infection, utilizing in vivo imaging of luciferase-expressing <jats:italic>P. berghei<\/jats:italic> (ANKA strain) sporozoites in female albino C57Bl\/6 mice. Parasitaemia was monitored by flow cytometry for up to 30\u00a0days post-infection.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Omadacycline demonstrated comparable in vitro activity to doxycycline against both drug-sensitive and drug-resistant <jats:italic>P. falciparum<\/jats:italic> clones, while doxycycline showed reduced activity against two drug-resistant clones. Notably, omadacycline exhibited superior anti-schizont activity in the <jats:italic>P. cynomolgi<\/jats:italic> liver stage assay. In the <jats:italic>P. berghei<\/jats:italic> murine model, omadacycline was efficacious in both liver and early blood stages compared to the untreated control group, and demonstrated improved survival compared to doxycycline.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Omadacycline demonstrated enhanced antimalarial efficacy over doxycycline in vitro in liver stage activity and in overcoming resistance in the blood stage, and in survival in an in vivo model of <jats:italic>P. berghei<\/jats:italic> infection. These findings support further investigation of omadacycline as a potential candidate for malaria prophylaxis and treatment.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12936-025-05448-w","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T04:39:58Z","timestamp":1750307998000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["In vitro activity and in vivo efficacy of omadacycline against Plasmodium species"],"prefix":"10.1186","volume":"24","author":[{"given":"Michael S.","family":"Madejczyk","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan E.","family":"Leed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl","family":"Kudyba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Roth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica L.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diane","family":"Anastasiou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica V.","family":"Pierce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alisa W.","family":"Serio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Caridha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"5448_CR1","first-page":"2024","volume-title":"addressing inequity in the global malaria response","author":"WHO. 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