{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:34:43Z","timestamp":1789004083050,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T00:00:00Z","timestamp":1687996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>M5717 is a promising antimalarial drug under development that acts against multiple stages of the life cycle of <jats:italic>Plasmodium<\/jats:italic> parasites by inhibiting the translation elongation factor 2 (<jats:italic>Pf<\/jats:italic>eEF2), thereby preventing protein synthesis. The parasite clearance profile after drug treatment in preclinical studies in mice, and clinical trials in humans showed a notable delayed clearance phenotype whereby parasite infected red blood cells (iRBCs) persisted in the bloodstream for a significant period before eventual clearance. In a normal <jats:italic>P. falciparum<\/jats:italic> infection iRBCs sequester in the deep circulation by cytoadherence, allowing them to avoid surveillance and clearance in the spleen. We found that M5717 blocks parasite modification of their host red blood cells (RBCs) by preventing synthesis of new exported proteins, rather than by directly blocking the export of these proteins into the RBC compartment. Using <jats:italic>in vitro<\/jats:italic> models, we demonstrated that M5717 treated ring\/trophozoite stage iRBCs became less rigid, and cytoadhered less well compared to untreated iRBCs. This indicates that <jats:italic>in vivo<\/jats:italic> persistence of M5717 treated iRBCs in the bloodstream is likely due to reduced cytoadherence and splenic clearance.<\/jats:p>","DOI":"10.3389\/fcimb.2023.1211613","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T17:40:25Z","timestamp":1688060425000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["The delayed bloodstream clearance of Plasmodium falciparum parasites after M5717 treatment is attributable to the inability to modify their red blood cell hosts"],"prefix":"10.3389","volume":"13","author":[{"given":"Molly","family":"Parkyn Schneider","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Looker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Rebelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Khoury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W. A.","family":"Dixon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Oeuvray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan S.","family":"Crabb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Gilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112571","article-title":"Plasmodium falciparum transfected with ultra bright NanoLuc luciferase offers high sensitivity detection for the screening of growth and cellular trafficking inhibitors","volume":"9","author":"Azevedo","year":"2014","journal-title":"PloS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/nature14451","article-title":"A novel multiple-stage antimalarial agent that inhibits protein synthesis","volume":"522","author":"Baragana","year":"2015","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"9672","DOI":"10.1021\/acs.jmedchem.6b00723","article-title":"Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy","volume":"59","author":"Baragana","year":"2016","journal-title":"J. Med. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/nature13574","article-title":"PTEX component HSP101 mediates export of diverse malaria effectors into host erythrocytes","volume":"511","author":"Beck","year":"2014","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"294","DOI":"10.3201\/eid2701.203527","article-title":"Increase in kelch 13 polymorphisms in Plasmodium falciparum, southern Rwanda","volume":"27","author":"Bergmann","year":"2021","journal-title":"Emerg. Infect. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1111\/tra.12053","article-title":"Role of plasmepsin V in export of diverse protein families from the Plasmodium falciparum exportome","volume":"14","author":"Boddey","year":"2013","journal-title":"Traffic"},{"key":"B7","doi-asserted-by":"publisher","first-page":"7871","DOI":"10.1074\/jbc.M111.328591","article-title":"Biosynthesis, localization, and macromolecular arrangement of the Plasmodium falciparum translocon of exported proteins (PTEX)","volume":"287","author":"Bullen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12936-016-1675-x","article-title":"New developments in anti-malarial target candidate and product profiles","volume":"16","author":"Burrows","year":"2017","journal-title":"Malar. J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1111\/tra.12577","article-title":"Spatial organization of protein export in malaria parasite blood stages","volume":"19","author":"Charnaud","year":"2018","journal-title":"Traffic"},{"key":"B10","doi-asserted-by":"publisher","first-page":"23332","DOI":"10.1074\/jbc.M112.348839","article-title":"Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate a in placental malaria","volume":"287","author":"Clausen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4040","DOI":"10.1182\/blood.V88.10.4040.bloodjournal88104040","article-title":"Adhesion of malaria-infected red blood cells to chondroitin sulfate a under flow conditions","volume":"88","author":"Cooke","year":"1996","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.23217.021","article-title":"Plasmodium parasites deploy RhopH2 into the host erythrocyte to obtain nutrients, grow and replicate","volume":"6","author":"Counihan","year":"2017","journal-title":"eLife"},{"key":"B13","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.ijpara.2020.01.002","article-title":"Screening the medicines for malaria venture pathogen box for invasion and egress inhibitors of the blood stage of Plasmodium falciparum reveals several inhibitory compounds","volume":"50","author":"Dans","year":"2020","journal-title":"Int. J. Parasitol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1038\/nature08104","article-title":"A newly discovered protein export machine in malaria parasites","volume":"459","author":"De Koning-Ward","year":"2009","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e88","DOI":"10.1182\/blood-2010-10-312801","article-title":"The sensing of poorly deformable red blood cells by the human spleen can be mimicked in vitro","volume":"117","author":"Deplaine","year":"2011","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"37502","DOI":"10.1038\/srep37502","article-title":"Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum","volume":"6","author":"Dickerman","year":"2016","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin resistance in Plasmodium falciparum malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.pt.2021.04.006","article-title":"Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials","volume":"37","author":"Duffey","year":"2021","journal-title":"Trends Parasitol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/nature13555","article-title":"PTEX is an essential nexus for protein export in malaria parasites","volume":"511","author":"Elsworth","year":"2014","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"10292","DOI":"10.1038\/s41598-019-46500-5","article-title":"A 4-cyano-3-methylisoquinoline inhibitor of plasmodium falciparum growth targets the sodium efflux pump PfATP4","volume":"9","author":"Gilson","year":"2019","journal-title":"Sci. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1182\/blood.V99.3.1060","article-title":"Contribution of parasite proteins to altered mechanical properties of malaria-infected red blood cells","volume":"99","author":"Glenister","year":"2002","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1038\/360352a0","article-title":"Inhibition by brefeldin a of a golgi membrane enzyme that catalyses exchange of guanine nucleotide bound to ARF","volume":"360","author":"Helms","year":"1992","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1934","DOI":"10.1126\/science.1102737","article-title":"A host-targeting signal in virulence proteins reveals a secretome in malarial infection","volume":"306","author":"Hiller","year":"2004","journal-title":"Science"},{"key":"B24","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/s41586-018-0469-4","article-title":"Malaria parasite translocon structure and mechanism of effector export","volume":"561","author":"Ho","year":"2018","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e23485","DOI":"10.7554\/eLife.23485.015","article-title":"An essential dual-function complex mediates erythrocyte invasion and channel-mediated nutrient uptake in malaria parasites","volume":"6","author":"Ito","year":"2017","journal-title":"Elife"},{"key":"B26","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.pt.2021.04.009","article-title":"Defining the essential exportome of the malaria parasite","volume":"37","author":"Jonsdottir","year":"2021","journal-title":"Trends Parasitol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.ijpddr.2021.06.004","article-title":"Surveillance of molecular markers of Plasmodium falciparum artemisinin resistance (kelch13 mutations) in Papua new Guinea between 2016 and 2018","volume":"16","author":"Lautu-Gumal","year":"2021","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"B28","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1111\/tra.12862","article-title":"The medicines for malaria venture malaria box contains inhibitors of protein secretion in Plasmodium falciparum blood stage parasites","volume":"23","author":"Looker","year":"2022","journal-title":"Traffic"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1084\/jem.168.4.1307","article-title":"Cytoadherence by Plasmodium falciparum-infected erythrocytes is correlated with the expression of a family of variable proteins on infected erythrocytes","volume":"168","author":"Magowan","year":"1988","journal-title":"J. Exp. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.cell.2008.04.051","article-title":"Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes","volume":"134","author":"Maier","year":"2008","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"205","DOI":"10.4269\/ajtmh.1993.48.205","article-title":"Measurement of the lactate dehydrogenase activity of Plasmodium falciparum as an assessment of parasitemia","volume":"48","author":"Makler","year":"1993","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B32","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1126\/science.aba0445","article-title":"Uncovering the ART of antimalarial resistance","volume":"367","author":"Marapana","year":"2020","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1126\/science.1102452","article-title":"Targeting malaria virulence and remodeling proteins to the host erythrocyte","volume":"306","author":"Marti","year":"2004","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1016\/S1473-3099(21)00252-8","article-title":"Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study","volume":"21","author":"Mccarthy","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"B35","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.cell.2011.05.002","article-title":"Malaria parasite clag3 genes determine channel-mediated nutrient uptake by infected red blood cells","volume":"145","author":"Nguitragool","year":"2011","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s42003-022-03290-3","article-title":"RhopH2 and RhopH3 export enables assembly of the RhopH complex on P. falciparum-infected erythrocyte membranes","volume":"5","author":"Pasternak","year":"2022","journal-title":"Commun. Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"31166","DOI":"10.1074\/jbc.M505298200","article-title":"Structural and functional studies of interaction between Plasmodium falciparum knob-associated histidine-rich protein (KAHRP) and erythrocyte spectrin","volume":"280","author":"Pei","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02181-19","article-title":"Preclinical antimalarial combination study of M5717, a Plasmodium falciparum elongation factor 2 inhibitor, and pyronaridine, a hemozoin formation inhibitor","volume":"64","author":"Rottmann","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"B39","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1182\/blood-2005-11-4624","article-title":"The role of KAHRP domains in knob formation and cytoadherence of P falciparum-infected human erythrocytes","volume":"108","author":"Rug","year":"2006","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","first-page":"R12","DOI":"10.1186\/gb-2006-7-2-r12","article-title":"Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites","volume":"7","author":"Sargeant","year":"2006","journal-title":"Genome Biol."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00404-22","article-title":"Kinetic tracking of Plasmodium falciparum antigens on infected erythrocytes with a novel reporter of protein insertion and surface exposure","volume":"13","author":"Shao","year":"2022","journal-title":"mBio"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.23239.017","article-title":"The Plasmodium falciparum rhoptry protein RhopH3 plays essential roles in host cell invasion and nutrient uptake","volume":"6","author":"Sherling","year":"2017","journal-title":"Elife"},{"key":"B43","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/0166-6851(87)90005-3","article-title":"Localization of Plasmodium falciparum histidine-rich protein 1 in the erythrocyte skeleton under knobs","volume":"25","author":"Taylor","year":"1987","journal-title":"Mol. Biochem. Parasitol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/S0006-3495(03)74836-X","article-title":"A two-compartment model of osmotic lysis in Plasmodium falciparum-infected erythrocytes","volume":"84","author":"Wagner","year":"2003","journal-title":"Biophys. J."},{"key":"B45","doi-asserted-by":"publisher","first-page":"102193","DOI":"10.1016\/j.mib.2022.102193","article-title":"Plasmodium falciparum resistance to artemisinin-based combination therapies","volume":"69","author":"Ward","year":"2022","journal-title":"Curr. Opin. Microbiol."},{"key":"B46","volume-title":"World malaria report","year":"2022"},{"key":"B47","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1186\/s12936-021-03933-6","article-title":"Increase in the proportion of Plasmodium falciparum with kelch13 C580Y mutation and decline in pfcrt and pfmdr1 mutant alleles in Papua new Guinea","volume":"20","author":"Yoshida","year":"2021","journal-title":"Malar. J."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2023.1211613\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T17:40:28Z","timestamp":1688060428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2023.1211613\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,29]]},"references-count":47,"alternative-id":["10.3389\/fcimb.2023.1211613"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2023.1211613","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,29]]},"article-number":"1211613"}}