{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:53:33Z","timestamp":1792788813322,"version":"4.5.0"},"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2019\/02171-3"],"award-info":[{"award-number":["2019\/02171-3"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2021\/13809-9"],"award-info":[{"award-number":["2021\/13809-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2017\/18611-7"],"award-info":[{"award-number":["2017\/18611-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2021\/06769-0"],"award-info":[{"award-number":["2021\/06769-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2018\/24878-9"],"award-info":[{"award-number":["2018\/24878-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["441038\/2020-4"],"award-info":[{"award-number":["441038\/2020-4"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["440373\/2022-0"],"award-info":[{"award-number":["440373\/2022-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["162117\/2018-3"],"award-info":[{"award-number":["162117\/2018-3"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI124678"],"award-info":[{"award-number":["R01AI124678"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R37AI050234"],"award-info":[{"award-number":["R37AI050234"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes od Health","award":["R01AI147628"],"award-info":[{"award-number":["R01AI147628"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI147628"],"award-info":[{"award-number":["R01AI147628"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005285","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Goi\u00e1s","doi-asserted-by":"publisher","award":["202010267000272"],"award-info":[{"award-number":["202010267000272"]}],"id":[{"id":"10.13039\/501100005285","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013275","name":"Instituto Serrapilheira","doi-asserted-by":"publisher","award":["G-1709-16618"],"award-info":[{"award-number":["G-1709-16618"]}],"id":[{"id":"10.13039\/501100013275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010434","name":"'la Caixa' Foundation","doi-asserted-by":"publisher","award":["HR21-848"],"award-info":[{"award-number":["HR21-848"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018693","name":"HORIZON EUROPE Framework Programme","doi-asserted-by":"publisher","award":["101080744"],"award-info":[{"award-number":["101080744"]}],"id":[{"id":"10.13039\/100018693","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2021-03667"],"award-info":[{"award-number":["2021-03667"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001728","name":"Swedish Foundation for International Cooperation in Research and Higher Education","doi-asserted-by":"publisher","award":["BR2018-8017"],"award-info":[{"award-number":["BR2018-8017"]}],"id":[{"id":"10.13039\/501100001728","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1054480"],"award-info":[{"award-number":["OPP1054480"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs. In this study, we characterized the asexual blood stage antiplasmodial activity and resistance mechanisms of LDT-623, a 4-aminoquinoline (4-AQ). We also detected LDT-623 activity against multiple stages (liver schizonts, stage IV-V gametocytes, and ookinetes) of\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    \u2019s life cycle, a feature unlike other 4-AQs such as chloroquine (CQ) and piperaquine (PPQ). Using heme fractionation profiling and drug uptake studies in PfCRT-containing proteoliposomes, we observed inhibition of hemozoin formation and PfCRT-mediated transport, which constitute characteristic features of 4-AQs\u2019 MoA. We also found minimal cross-resistance to LDT-623 in a panel of mutant\n                    <jats:italic>pfcrt<\/jats:italic>\n                    or\n                    <jats:italic>pfmdr1<\/jats:italic>\n                    lines, but not the PfCRT F145I mutant that is highly resistant to PPQ resistance yet is very unfit. No\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    parasites were recovered in an\n                    <jats:italic>in vitro<\/jats:italic>\n                    resistance selection study, suggesting a high barrier for resistance to emerge. Finally, a competitive growth assay comprising &gt;50 barcoded parasite lines with mutated resistance mediators or major drug targets found no evidence of cross-resistance. Our findings support further exploration of this promising 4-AQ.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012627","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T13:38:24Z","timestamp":1730209104000},"page":"e1012627","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants"],"prefix":"10.1371","volume":"20","author":[{"given":"Let\u00edcia Tiburcio","family":"Ferreira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Capatti","family":"Cassiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Carlos Salazar","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Okombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Calit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Fontinha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Gil-Iturbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Coyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina Horta","family":"Andrade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Sunnerhagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Youssef","family":"Bargieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Prud\u00eancio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Quick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro V.","family":"Cravo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus C. S.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9969-7300","authenticated-orcid":true,"given":"Fabio Trindade Maranh\u00e3o","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"ppat.1012627.ref001","unstructured":"World Health Organization. World Malaria Report 2023. 2023."},{"key":"ppat.1012627.ref002","first-page":"742","article-title":"A molecular marker of artemisinin-resistant Plasmodium falciparum malaria","volume":"57","author":"F Ariey","year":"2014","journal-title":"Nature"},{"key":"ppat.1012627.ref003","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/S1473-3099(19)30391-3","article-title":"Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study","volume":"19","author":"RW van der Pluijm","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012627.ref004","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1016\/S1473-3099(20)30228-0","article-title":"Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study","volume":"20","author":"M Imwong","year":"2020","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012627.ref005","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1056\/NEJMoa2211803","article-title":"Evolution of partial resistance to artemisinins in malaria parasites in Uganda","volume":"389","author":"MD Conrad","year":"2023","journal-title":"N Engl J Med"},{"issue":"10","key":"ppat.1012627.ref006","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1038\/s41564-023-01461-4","article-title":"Plasmodium falciparum resistant to artemisinin and diagnostics have emerged in Ethiopia","volume":"8","author":"AA Fola","year":"2023","journal-title":"Nat Microbiol"},{"key":"ppat.1012627.ref007","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1056\/NEJMoa2210956","article-title":"Increasing prevalence of artemisinin-resistant HRP2-negative malaria in Eritrea","volume":"389","author":"S Mihreteab","year":"2023","journal-title":"N Engl J Med"},{"key":"ppat.1012627.ref008","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1016\/S0140-6736(12)60484-X","article-title":"Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study","volume":"379","author":"AP Phyo","year":"2012","journal-title":"The Lancet"},{"key":"ppat.1012627.ref009","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1186\/1475-2875-10-339","article-title":"Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator","volume":"10","author":"JA Flegg","year":"2011","journal-title":"Malar J"},{"key":"ppat.1012627.ref010","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin resistance in Plasmodium falciparum malaria","volume":"361","author":"AM Dondorp","year":"2009","journal-title":"N Engl J Med"},{"key":"ppat.1012627.ref011","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/S1473-3099(13)70252-4","article-title":"Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies","volume":"13","author":"B Witkowski","year":"2013","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012627.ref012","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.lfs.2006.11.008","article-title":"Antimalarial drugs inhibiting hemozoin (\u03b2-hematin) formation: A mechanistic update","volume":"80","author":"S Kumar","year":"2007","journal-title":"Life Sci"},{"key":"ppat.1012627.ref013","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1021\/acs.accounts.1c00154","article-title":"Heme Detoxification in the malaria parasite: a target for antimalarial drug development","volume":"54","author":"KA de Villiers","year":"2021","journal-title":"Acc Chem Res"},{"key":"ppat.1012627.ref014","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1021\/jm020858u","article-title":"Structure-activity relationships in 4-aminoquinoline antiplasmodials. The role of the group at the 7-position","volume":"45","author":"CH Kaschula","year":"2002","journal-title":"J Med Chem"},{"key":"ppat.1012627.ref015","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1021\/jm990437l","article-title":"Structure-function relationships in aminoquinolines: Effect of amino and chloro groups on quinoline-hematin complex formation, inhibition of \u03b2- hematin formation, and antiplasmodial activity","volume":"43","author":"TJ Egan","year":"2000","journal-title":"J Med Chem"},{"key":"ppat.1012627.ref016","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1146\/annurev-micro-020518-115546","article-title":"Molecular mechanisms of drug resistance in Plasmodium falciparum malaria","volume":"74","author":"KJ Wicht","year":"2020","journal-title":"Annu Rev Microbiol"},{"key":"ppat.1012627.ref017","doi-asserted-by":"crossref","first-page":"e0110122","DOI":"10.1128\/spectrum.01101-22","article-title":"The knock-down of the chloroquine resistance transporter PfCRT is linked to oligopeptide handling in Plasmodium falciparum","volume":"10","author":"CP Sanchez","year":"2022","journal-title":"Microbiol Spectr"},{"key":"ppat.1012627.ref018","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S1097-2765(05)00077-8","article-title":"Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance","volume":"6","author":"D Fidock","year":"2000","journal-title":"Mol Cell"},{"key":"ppat.1012627.ref019","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1038\/s41467-018-05652-0","article-title":"Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine","volume":"9","author":"LS Ross","year":"2018","journal-title":"Nat Commun"},{"key":"ppat.1012627.ref020","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41586-019-1795-x","article-title":"Structure and drug resistance of the Plasmodium falciparum transporter PfCRT","volume":"576","author":"J Kim","year":"2019","journal-title":"Nature"},{"key":"ppat.1012627.ref021","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1021\/cb4008953","article-title":"Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum","volume":"9","author":"CA Hrycyna","year":"2014","journal-title":"ACS Chem Biol"},{"key":"ppat.1012627.ref022","doi-asserted-by":"crossref","first-page":"115458","DOI":"10.1016\/j.ejmech.2023.115458","article-title":"Recent developments in antimalarial activities of 4-aminoquinoline derivatives","volume":"256","author":"L Ravindar","year":"2023","journal-title":"Eur J Med Chem"},{"key":"ppat.1012627.ref023","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3390\/biom11030459","article-title":"QSAR-based virtual screening of natural products database for identification of potent antimalarial hits","volume":"11","author":"LT Ferreira","year":"2021","journal-title":"Biomolecules"},{"key":"ppat.1012627.ref024","doi-asserted-by":"crossref","first-page":"418","DOI":"10.2307\/3280287","article-title":"Synchronization of Plasmodium falciparum erythrocytic stages in culture","volume":"65","author":"C Lambros","year":"1979","journal-title":"J Parasitol"},{"key":"ppat.1012627.ref025","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays","volume":"65","author":"T. Mosmann","year":"1983","journal-title":"J Immunol Methods"},{"key":"ppat.1012627.ref026","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.molbiopara.2012.10.004","article-title":"A transgenic Plasmodium falciparum NF54 strain that expresses GFP-luciferase throughout the parasite life cycle","volume":"186","author":"AM Vaughan","year":"2012","journal-title":"Mol Biochem Parasitol"},{"key":"ppat.1012627.ref027","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.molbiopara.2007.04.008","article-title":"Improved synchronous production of Plasmodium falciparum gametocytes in vitro","volume":"154","author":"QL Fivelman","year":"2007","journal-title":"Mol Biochem Parasitol"},{"key":"ppat.1012627.ref028","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acsinfecdis.5b00143","article-title":"High-throughput luciferase-based assay for the discovery of therapeutics that prevent malaria","volume":"2","author":"J Swann","year":"2016","journal-title":"ACS Infect Dis"},{"key":"ppat.1012627.ref029","doi-asserted-by":"crossref","first-page":"e1053","DOI":"10.1128\/AAC.01053-18","article-title":"Screening the Pathogen Box against Plasmodium sexual stages using a new nanoluciferase based transgenic line of P. berghei identifies transmission-blocking compounds","volume":"62","author":"J Calit","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"ppat.1012627.ref030","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1084\/jem.189.12.1947","article-title":"Structure and expression of an adhesive protein\u2013like molecule of mosquito invasive-stage malarial parasite","volume":"189","author":"M Yuda","year":"1999","journal-title":"J Exp Med"},{"key":"ppat.1012627.ref031","first-page":"1","article-title":"Visualization and quantitative analysis of the rodent malaria liver stage by real-time imaging","volume":"4","author":"IHJ Ploemen","year":"2009","journal-title":"PLoS One"},{"key":"ppat.1012627.ref032","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/978-1-0716-0724-4_4","volume-title":"Biophysics of membrane proteins: methods and protocols","author":"A Bazzone","year":"2020"},{"key":"ppat.1012627.ref033","doi-asserted-by":"crossref","first-page":"e2302799120","DOI":"10.1073\/pnas.2302799120","article-title":"Insight into the mechanism of H+-coupled nucleobase transport","volume":"120","author":"J Weng","year":"2023","journal-title":"Proc Natl Acad Sci USA"},{"key":"ppat.1012627.ref034","first-page":"179","article-title":"Experimentally observed effects of carriers on the electrical properties of bilayer membranes\u2014equilibrium domain. With a contribution on the molecular basis of ion selectivity","volume":"2","author":"G Szabo","year":"1973","journal-title":"Membranes"},{"key":"ppat.1012627.ref035","doi-asserted-by":"crossref","first-page":"11083","DOI":"10.1021\/bi980684b","article-title":"Unidirectional reconstitution and characterization of purified Na+\/proline transporter of Escherichia coli","volume":"37","author":"H Jung","year":"1998","journal-title":"Biochemistry"},{"key":"ppat.1012627.ref036","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1186\/s12936-015-0729-9","article-title":"Optimization of a multi-well colorimetric assay to determine haem species in Plasmodium falciparum in the presence of anti-malarials","volume":"14","author":"JM Combrinck","year":"2015","journal-title":"Malar J"},{"key":"ppat.1012627.ref037","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/978-1-4939-9550-9_9","article-title":"Plasmodium falciparum in vitro drug resistance selections and gene editing","volume":"2013","author":"CL Ng","year":"2019","journal-title":"Methods Mol Biol"},{"key":"ppat.1012627.ref038","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1038\/s41467-023-38774-1","article-title":"Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum","volume":"14","author":"K K\u00fcmpornsin","year":"2023","journal-title":"Nat Commun"},{"key":"ppat.1012627.ref039","doi-asserted-by":"crossref","first-page":"14240","DOI":"10.1038\/ncomms14240","article-title":"Esterase mutation is a mechanism of resistance to antimalarial compounds","volume":"8","author":"ES Istvan","year":"2017","journal-title":"Nat Commun"},{"key":"ppat.1012627.ref040","doi-asserted-by":"crossref","DOI":"10.1128\/mbio.00937-22","article-title":"Barcoding genetically distinct Plasmodium falciparum strains for comparative assessment of fitness and antimalarial drug resistance","volume":"13","author":"M Carrasquilla","year":"2022","journal-title":"mBio"},{"key":"ppat.1012627.ref041","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.chom.2015.12.001","article-title":"High-throughput assay and discovery of small molecules that interrupt malaria transmission","volume":"19","author":"DM Plouffe","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ppat.1012627.ref042","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12915-022-01374-4","article-title":"The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures","volume":"20","author":"I Bouz\u00f3n-Arn\u00e1iz","year":"2022","journal-title":"BMC Biol"},{"key":"ppat.1012627.ref043","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.4155\/fmc.13.113","article-title":"Hemozoin and antimalarial drug discovery","volume":"5","author":"KY Fong","year":"2013","journal-title":"Future Med Chem"},{"key":"ppat.1012627.ref044","doi-asserted-by":"crossref","first-page":"7483","DOI":"10.1073\/pnas.1708153114","article-title":"Quinolines block every step of malaria heme crystal growth","volume":"114","author":"DJ Sullivan","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"ppat.1012627.ref045","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.chom.2012.12.006","article-title":"Na+ regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials","volume":"13","author":"NJ Spillman","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ppat.1012627.ref046","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1021\/acs.biochem.0c00247","article-title":"Altered drug transport by Plasmodium falciparum chloroquine resistance transporter isoforms harboring mutations associated with piperaquine resistance","volume":"59","author":"B Riegel","year":"2020","journal-title":"Biochemistry"},{"key":"ppat.1012627.ref047","doi-asserted-by":"crossref","first-page":"11672","DOI":"10.1073\/pnas.1507142112","article-title":"Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt","volume":"112","author":"S Pelleau","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"ppat.1012627.ref048","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1038\/ncomms5029","article-title":"Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action","volume":"5","author":"D Birth","year":"2014","journal-title":"Nat Commun"},{"key":"ppat.1012627.ref049","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0166-6851(86)90066-6","article-title":"Altered dihydrofolate reductase in pyrimethamine-resistant Plasmodium falciparum","volume":"19","author":"RD Walter","year":"1986","journal-title":"Mol Biochem Parasitol"},{"key":"ppat.1012627.ref050","doi-asserted-by":"crossref","first-page":"e27829","DOI":"10.7554\/eLife.27829","article-title":"Structure-based analysis of CysZ-mediated cellular uptake of sulfate","volume":"7","author":"Z Assur Sanghai","year":"2018","journal-title":"eLife"},{"key":"ppat.1012627.ref051","doi-asserted-by":"crossref","first-page":"e1010278","DOI":"10.1371\/journal.ppat.1010278","article-title":"Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance","volume":"18","author":"JL Small-Saunders","year":"2022","journal-title":"PLoS Pathog"},{"key":"ppat.1012627.ref052","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/S1473-3099(19)30543-2","article-title":"Plasmodium falciparum resistance to piperaquine driven by PfCRT","volume":"19","author":"SK Dhingra","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012627.ref053","doi-asserted-by":"crossref","first-page":"e02731","DOI":"10.1128\/mBio.02731-18","article-title":"Global spread of mutant PfCRT and its pleiotropic impact on Plasmodium falciparum multidrug resistance and fitness","volume":"10","author":"SK Dhingra","year":"2019","journal-title":"mBio"},{"key":"ppat.1012627.ref054","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1086\/507115","article-title":"Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin","volume":"194","author":"ABS Sidhu","year":"2006","journal-title":"J Infect Dis"},{"key":"ppat.1012627.ref055","doi-asserted-by":"crossref","first-page":"11553","DOI":"10.1038\/ncomms11553","article-title":"Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies","volume":"7","author":"MI Veiga","year":"2016","journal-title":"Nat Commun"},{"key":"ppat.1012627.ref056","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00436-006-0246-4","article-title":"Linkage disequilibrium between two distinct loci in chromosomes 5 and 7 of Plasmodium falciparum and in vivo chloroquine resistance in Southwest Nigeria","volume":"100","author":"CT Happi","year":"2006","journal-title":"Parasitol Res"},{"key":"ppat.1012627.ref057","doi-asserted-by":"crossref","first-page":"18883","DOI":"10.1073\/pnas.0911317106","article-title":"Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine","volume":"106","author":"JM S\u00e1","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"ppat.1012627.ref058","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1038\/s41467-018-04104-z","article-title":"Plasmepsin II\u2013III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum","volume":"9","author":"S Bopp","year":"2018","journal-title":"Nat Commun"},{"key":"ppat.1012627.ref059","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.1093\/bioinformatics\/bth358","article-title":"TMRPres2D: high quality visual representation of transmembrane protein models","volume":"20","author":"IC Spyropoulos","year":"2004","journal-title":"Bioinformatics"},{"key":"ppat.1012627.ref060","doi-asserted-by":"crossref","first-page":"11901","DOI":"10.1038\/ncomms11901","article-title":"A broad analysis of resistance development in the malaria parasite","volume":"7","author":"VC Corey","year":"2016","journal-title":"Nat Commun"},{"key":"ppat.1012627.ref061","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1126\/science.aan4472","article-title":"Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics","volume":"359","author":"AN Cowell","year":"2018","journal-title":"Science"},{"key":"ppat.1012627.ref062","doi-asserted-by":"crossref","first-page":"2764","DOI":"10.1021\/acsinfecdis.1c00322","article-title":"Prioritization of molecular targets for antimalarial drug discovery","volume":"7","author":"B Forte","year":"2021","journal-title":"ACS Infect Dis"},{"key":"ppat.1012627.ref063","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nature12782","article-title":"Targeting Plasmodium PI(4)K to eliminate malaria","volume":"504","author":"CW McNamara","year":"2013","journal-title":"Nature"},{"key":"ppat.1012627.ref064","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nature14451","article-title":"A novel multiple-stage antimalarial agent that inhibits protein synthesis","volume":"522","author":"B Baraga\u00f1a","year":"2015","journal-title":"Nature"},{"key":"ppat.1012627.ref065","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nature09107","article-title":"Thousands of chemical starting points for antimalarial lead identification","volume":"465","author":"FJ Gamo","year":"2010","journal-title":"Nature"},{"key":"ppat.1012627.ref066","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.51015","article-title":"Local emergence in Amazonia of Plasmodium falciparum K13 C580Y mutants associated with in vitro artemisinin resistance","volume":"9","author":"LC Mathieu","year":"2020","journal-title":"eLife"},{"key":"ppat.1012627.ref067","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S1473-3099(23)00502-9","article-title":"Impact of piperaquine resistance in Plasmodium falciparum on malaria treatment effectiveness in The Guianas: a descriptive epidemiological study","volume":"24","author":"C Florimond","year":"2024","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012627.ref068","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1093\/gbe\/evx126","article-title":"Partner-drug resistance and population substructuring of artemisinin-resistant Plasmodium falciparum in Cambodia","volume":"9","author":"CM Parobek","year":"2017","journal-title":"Genome Biol Evol"},{"key":"ppat.1012627.ref069","doi-asserted-by":"crossref","first-page":"4719","DOI":"10.1128\/AAC.00835-15","article-title":"Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in western Cambodia: dihydroartemisinin-piperaquine open-label multicenter clinical assessment","volume":"59","author":"R Leang","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"ppat.1012627.ref070","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1086\/596738","article-title":"In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa","volume":"199","author":"C Sisowath","year":"2009","journal-title":"J Infect Dis"},{"key":"ppat.1012627.ref071","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1093\/infdis\/jiu141","article-title":"Comparative impacts over 5 years of artemisinin-based combination therapies on Plasmodium falciparum polymorphisms that modulate drug sensitivity in Ugandan children","volume":"210","author":"MD Conrad","year":"2014","journal-title":"J Infect Dis"},{"key":"ppat.1012627.ref072","doi-asserted-by":"crossref","first-page":"833","DOI":"10.4269\/ajtmh.14-0031","article-title":"Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine","volume":"91","author":"M Venkatesan","year":"2014","journal-title":"Am J Trop Med Hyg"},{"key":"ppat.1012627.ref073","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1093\/molbev\/msv282","article-title":"Population structure shapes copy number variation in malaria parasites","volume":"33","author":"IH Cheeseman","year":"2016","journal-title":"Mol Biol Evol"},{"key":"ppat.1012627.ref074","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.chembiol.2020.01.001","article-title":"The antimalarial natural product Salinipostin A identifies essential \u03b1\/\u03b2 serine hydrolases involved in lipid metabolism in P. falciparum parasites","volume":"27","author":"E Yoo","year":"2020","journal-title":"Cell Chem Biol"},{"key":"ppat.1012627.ref075","doi-asserted-by":"crossref","first-page":"9371","DOI":"10.1021\/acs.jmedchem.8b01333","article-title":"Antimalarial lead-optimization studies on a 2,6-imidazopyridine series within a constrained chemical space to circumvent atypical dose-response curves against multidrug-resistant parasite strains","volume":"61","author":"C Le Manach","year":"2018","journal-title":"J Med Chem"},{"key":"ppat.1012627.ref076","doi-asserted-by":"crossref","first-page":"35078","DOI":"10.1074\/jbc.M804990200","article-title":"Identification and characterization of small molecule inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase","volume":"283","author":"V Patel","year":"2008","journal-title":"J Biol Chem"},{"key":"ppat.1012627.ref077","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nm.4381","article-title":"Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic","volume":"23","author":"B Blasco","year":"2017","journal-title":"Nat Med"},{"key":"ppat.1012627.ref078","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1186\/s12936-016-1511-3","article-title":"A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study","volume":"15","author":"JS McCarthy","year":"2016","journal-title":"Malar J"},{"key":"ppat.1012627.ref079","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1016\/S1473-3099(15)00079-1","article-title":"Ferroquine and artesunate in African adults and children with Plasmodium falciparum malaria: a phase 2, multicentre, randomised, double-blind, dose-ranging, non-inferiority study","volume":"15","author":"J Held","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012627.ref080","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/S1473-3099(15)00148-6","article-title":"Ferroquine: welcome to the next generation of antimalarials","volume":"15","author":"TN Wells","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012627.ref081","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-022-04420-2","article-title":"Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria","volume":"22","author":"A Gansane","year":"2023","journal-title":"Malar J"},{"key":"ppat.1012627.ref082","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.1128\/AAC.00358-10","article-title":"Amodiaquine resistance in Plasmodium falciparum malaria in Afghanistan is associated with the pfcrt SVMNT allele at codons 72 to 76","volume":"54","author":"K Beshir","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"ppat.1012627.ref083","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/nature07937","article-title":"Discovery of dual function acridones as a new antimalarial chemotype","volume":"459","author":"JX Kelly","year":"2009","journal-title":"Nature"},{"key":"ppat.1012627.ref084","doi-asserted-by":"crossref","first-page":"e01913","DOI":"10.1128\/AAC.01913-16","article-title":"Simplified reversed chloroquines to overcome malaria resistance to quinoline-based drugs","volume":"61","author":"B Gunsaru","year":"2017","journal-title":"Antimicrob Agents Chemother"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012627","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T13:38:51Z","timestamp":1730209131000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012627"}},"subtitle":[],"editor":[{"given":"Liwang","family":"Cui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,10,29]]},"references-count":84,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1012627","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,29]]}}}