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Accordingly, a PA analog \u03b1-PanAm showed potent activity against blood stage parasites<jats:italic>in vitro<\/jats:italic>; however, its efficacy<jats:italic>in vivo<\/jats:italic>and its mode of action remain unknown. We developed a new synthesis route for \u03b1-PanAm and showed that the compound is highly effective against blood stages of drug-sensitive and -resistant<jats:italic>P. falciparum<\/jats:italic>strains, inhibits development of<jats:italic>P. berghei<\/jats:italic>in hepatocytes, and at doses up to 100\u2009mg\/kg also inhibits blood stage development of<jats:italic>P. chabaudi<\/jats:italic>in mice. We used yeast and its pantothenate kinase Cab1 as models to characterize mode of action of \u03b1-PanAm and found that \u03b1-PanAm inhibits yeast growth in a PA-dependent manner, and its potency increases dramatically in a yeast mutant with defective pantothenate kinase activity. Biochemical analyses using<jats:sup>14<\/jats:sup>C-PA as a substrate demonstrated that \u03b1-PanAm is a competitive inhibitor of Cab1. Interestingly, biochemical and mass spectrometry analyses also showed that the compound is phosphorylated by Cab1. Together, these data suggest that \u03b1-PanAm exerts its antimicrobial activity by direct competition with the natural substrate PA for phosphorylation by the pantothenate kinase.<\/jats:p>","DOI":"10.1038\/s41598-017-14074-9","type":"journal-article","created":{"date-parts":[[2017,10,23]],"date-time":"2017-10-23T17:35:22Z","timestamp":1508780122000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The antimalarial activity of the pantothenamide \u03b1-PanAm is via inhibition of pantothenate phosphorylation"],"prefix":"10.1038","volume":"7","author":[{"given":"Joy E.","family":"Chiu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose","family":"Thekkiniath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae-Yeon","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin A.","family":"Perrin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Lawres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Plummer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Azan Z.","family":"Virji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanah","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin Y.","family":"Toh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael Van","family":"Zandt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed S. 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