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We report that the piperazine\u2010containing compound ACT\u2010451840 exhibits single\u2010digit nanomolar inhibition of the <jats:italic>Plasmodium falciparum<\/jats:italic> asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of <jats:italic>in vitro<\/jats:italic>\u2010derived ACT\u2010451840\u2010resistant parasites revealed single nucleotide polymorphisms in <jats:italic>pfmdr1<\/jats:italic>, which encodes a digestive vacuole membrane\u2010bound ATP\u2010binding cassette transporter known to alter <jats:italic>P. falciparum<\/jats:italic> susceptibility to multiple first\u2010line antimalarials. CRISPR\u2010Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT\u2010451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9\u2010introduced <jats:italic>pfmdr1<\/jats:italic> mutations also acquired ACT\u2010451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease\u2010relieving and transmission\u2010blocking antimalarials.<\/jats:p>","DOI":"10.1111\/mmi.13397","type":"journal-article","created":{"date-parts":[[2016,4,13]],"date-time":"2016-04-13T03:17:26Z","timestamp":1460517446000},"page":"381-393","source":"Crossref","is-referenced-by-count":70,"title":["CRISPR\u2010Cas9\u2010modified <i>pfmdr1<\/i> protects <i>Plasmodium falciparum<\/i> asexual blood stages and gametocytes against a class of piperazine\u2010containing compounds but potentiates artemisinin\u2010based combination therapy partner drugs"],"prefix":"10.1111","volume":"101","author":[{"given":"Caroline L.","family":"Ng","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Columbia University Medical Center New York NY 10032 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Siciliano","sequence":"additional","affiliation":[{"name":"Dipartimento di Malattie Infettive, Parassitarie ed Immunomediate, Istituto Superiore di Sanit\u00e0 00161 Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus C. 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