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Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite\u2019s growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two<jats:italic>P. falciparum<\/jats:italic>choline kinase inhibitors both<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. The compounds present distinct binding modes to the choline\/ethanolamine-binding site of<jats:italic>P. falciparum<\/jats:italic>choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the<jats:italic>P. falciparum<\/jats:italic>choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within<jats:italic>P. falciparum,<\/jats:italic>which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting<jats:italic>P. falciparum<\/jats:italic>choline kinase.<\/jats:p>","DOI":"10.1038\/srep33189","type":"journal-article","created":{"date-parts":[[2016,9,12]],"date-time":"2016-09-12T09:44:23Z","timestamp":1473673463000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death"],"prefix":"10.1038","volume":"6","author":[{"given":"Luc\u00eda","family":"Serr\u00e1n-Aguilera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Denton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Rubio-Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borja","family":"L\u00f3pez-Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Entrena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Izquierdo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry K.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Conejo-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Hurtado-Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,9,12]]},"reference":[{"key":"BFsrep33189_CR1","unstructured":"World Malaria Report. 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