{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:15:18Z","timestamp":1791296118225,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,9,15]],"date-time":"2014-09-15T00:00:00Z","timestamp":1410739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2014,10]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>The antimalarial spiroindolones disrupt <jats:styled-content style=\"fixed-case\"><jats:italic>P<\/jats:italic><\/jats:styled-content><jats:italic>lasmodium falciparum<\/jats:italic>\u2005<jats:styled-content style=\"fixed-case\"><jats:roman>Na<jats:sup>+<\/jats:sup><\/jats:roman><\/jats:styled-content> regulation and induce an alkalinization of the parasite cytosol. It has been proposed that they do so by inhibiting <jats:styled-content style=\"fixed-case\">PfATP<\/jats:styled-content>4, a parasite plasma membrane <jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>\u2010type <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase postulated to export <jats:styled-content style=\"fixed-case\"><jats:roman>Na<jats:sup>+<\/jats:sup><\/jats:roman><\/jats:styled-content> and import <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content><jats:sup>+<\/jats:sup> equivalents. Here, we screened the 400 antiplasmodial compounds of the open access \u2018<jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>alaria <jats:styled-content style=\"fixed-case\">B<\/jats:styled-content>ox\u2019 for their effects on parasite ion regulation. <jats:italic>Twenty eight<\/jats:italic> compounds affected parasite <jats:styled-content style=\"fixed-case\"><jats:roman>Na<jats:sup>+<\/jats:sup><\/jats:roman><\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content> regulation in a manner consistent with <jats:styled-content style=\"fixed-case\">PfATP<\/jats:styled-content>4 inhibition. Six of these, with chemically diverse structures, were selected for further analysis. All six showed reduced antiplasmodial activity against spiroindolone\u2010resistant parasites carrying mutations in <jats:styled-content style=\"fixed-case\"><jats:italic>pfatp4<\/jats:italic><\/jats:styled-content>. We exposed parasites to incrementally increasing concentrations of two of the six compounds and in both cases obtained resistant parasites with mutations in <jats:styled-content style=\"fixed-case\"><jats:italic>pfatp4<\/jats:italic><\/jats:styled-content>. The finding that diverse chemotypes have an apparently similar mechanism of action indicates that <jats:styled-content style=\"fixed-case\">PfATP<\/jats:styled-content>4 may be a significant Achilles' heel for the parasite.<\/jats:p>","DOI":"10.1111\/mmi.12765","type":"journal-article","created":{"date-parts":[[2014,8,22]],"date-time":"2014-08-22T09:35:35Z","timestamp":1408700135000},"page":"327-339","source":"Crossref","is-referenced-by-count":95,"title":["Diverse chemotypes disrupt ion homeostasis in the malaria parasite"],"prefix":"10.1111","volume":"94","author":[{"given":"Adele M.","family":"Lehane","sequence":"first","affiliation":[{"name":"Research School of Biology Australian National University  Canberra ACT 0200 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie C.","family":"Ridgway","sequence":"additional","affiliation":[{"name":"Research School of Biology Australian National University  Canberra ACT 0200 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen","family":"Baker","sequence":"additional","affiliation":[{"name":"Research School of Biology Australian National University  Canberra ACT 0200 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiaran","family":"Kirk","sequence":"additional","affiliation":[{"name":"Research School of Biology Australian National University  Canberra ACT 0200 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