{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:52:31Z","timestamp":1792018351308,"version":"4.4.0"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2016,7,5]],"date-time":"2016-07-05T00:00:00Z","timestamp":1467676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,9,7]],"date-time":"2016-09-07T00:00:00Z","timestamp":1473206400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Singapore International Economic Development Board"},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI103058"],"award-info":[{"award-number":["R01AI103058"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI090141"],"award-info":[{"award-number":["R01AI090141"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002112","name":"A.P. Giannini Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002112","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2016,9,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Mutations in the\n            <jats:named-content content-type=\"genus-species\">Plasmodium falciparum<\/jats:named-content>\n            cyclic amine resistance locus (PfCARL) are associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that display both prophylactic and transmission-blocking activity, in addition to activity against blood-stage parasites. Here, we show that\n            <jats:italic>pfcarl<\/jats:italic>\n            encodes a protein, with a predicted molecular weight of 153\u00a0kDa, that localizes to the\n            <jats:italic>cis<\/jats:italic>\n            -Golgi apparatus of the parasite in both asexual and sexual blood stages. Utilizing clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene introduction of 5 variants (L830V, S1076N\/I, V1103L, and I1139K), we demonstrate that mutations in\n            <jats:italic>pfcarl<\/jats:italic>\n            are sufficient to generate resistance against the imidazolopiperazines in both asexual and sexual blood-stage parasites. We further determined that the mutant PfCARL protein confers resistance to several structurally unrelated compounds. These data suggest that PfCARL modulates the levels of small-molecule inhibitors that affect Golgi-related processes, such as protein sorting or membrane trafficking, and is therefore an important mechanism of resistance in malaria parasites.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Several previous\n            <jats:italic>in vitro<\/jats:italic>\n            evolution studies have implicated the\n            <jats:named-content content-type=\"genus-species\">Plasmodium falciparum<\/jats:named-content>\n            cyclic amine resistance locus (PfCARL) as a potential target of imidazolopiperazines, potent antimalarial compounds with broad activity against different parasite life cycle stages. Given that the imidazolopiperazines are currently being tested in clinical trials, understanding their mechanism of resistance and the cellular processes involved will allow more effective clinical usage.\n          <\/jats:p>","DOI":"10.1128\/mbio.00696-16","type":"journal-article","created":{"date-parts":[[2016,7,6]],"date-time":"2016-07-06T01:49:35Z","timestamp":1467769775000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":75,"title":["Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance"],"prefix":"10.1128","volume":"7","author":[{"given":"Gregory","family":"LaMonte","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle Yi-Xiu","family":"Lim","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, Singapore, Singapore"},{"name":"National University of Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Wree","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Reimer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Nachon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Corey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Gedeck","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Plouffe","sequence":"additional","affiliation":[{"name":"Genomics Institute of the Novartis Research Foundation, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelissa","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Yeung","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Bifani","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, Singapore, Singapore"},{"name":"National University of Singapore, Singapore"},{"name":"Genomics Institute of the Novartis Research Foundation, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Winzeler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"World malaria report: 2014","author":"World Health Organization","year":"2015","unstructured":"World Health Organization. 2015. 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