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We show here that\n                    <jats:italic>S. cerevisiae<\/jats:italic>\n                    also acquires mutations in a gene encoding a P-type ATPase (\n                    <jats:italic>ScPMA1<\/jats:italic>\n                    ) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in\n                    <jats:italic>ScPMA1<\/jats:italic>\n                    do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace\n                    <jats:italic>Sc<\/jats:italic>\n                    Pma1p from the plasma membrane. Using an\n                    <jats:italic>in vitro<\/jats:italic>\n                    cell-free assay, we demonstrate that KAE609 directly inhibits\n                    <jats:italic>Sc<\/jats:italic>\n                    Pma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a\n                    <jats:italic>Sc<\/jats:italic>\n                    Pma1p homology model identifies a binding mode that supports genetic resistance determinants and\n                    <jats:italic>in vitro<\/jats:italic>\n                    experimental structure-activity relationships in both\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    and\n                    <jats:italic>S. cerevisiae<\/jats:italic>\n                    . This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.\n                  <\/jats:p>","DOI":"10.1038\/srep27806","type":"journal-article","created":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T05:35:12Z","timestamp":1465796112000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor"],"prefix":"10.1038","volume":"6","author":[{"given":"Gregory M.","family":"Goldgof","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob D.","family":"Durrant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Ottilie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Vigil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth E.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"Gunawan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim","family":"Kostylev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiersten A.","family":"Henderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake","family":"Schenken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"LaMonte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micah J.","family":"Manary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Murao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Nachon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximo","family":"Prescott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Case W.","family":"McNamara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn W.","family":"Slayman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rommie E.","family":"Amaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yo","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Winzeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,6,13]]},"reference":[{"key":"BFsrep27806_CR1","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1056\/NEJMoa1315860","volume":"371","author":"NJ White","year":"2014","unstructured":"White, N. 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