{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T07:17:12Z","timestamp":1793344632999,"version":"4.5.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,24]],"date-time":"2017-05-24T00:00:00Z","timestamp":1495584000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,24]],"date-time":"2017-05-24T00:00:00Z","timestamp":1495584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type\n                    <jats:italic>) Plasmodium falciparum<\/jats:italic>\n                    strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance. Here, we evaluate the\n                    <jats:italic>in vitro<\/jats:italic>\n                    drug sensitivity profile of normally-developing\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    ring stages and DHA-pretreated dormant rings (DP-rings) using a panel of antimalarial drugs, including the\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. We report that while KDU691 shows no activity against rings, it is highly inhibitory against DP-rings; a drug effect opposite to that of ART. Moreover, we provide evidence that KDU691 also kills DP-rings of\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    ART-resistant strains expressing mutant K13.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-02440-6","type":"journal-article","created":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T06:04:11Z","timestamp":1495087451000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["The Plasmodium PI(4)K inhibitor KDU691 selectively inhibits dihydroartemisinin-pretreated Plasmodium falciparum ring-stage parasites"],"prefix":"10.1038","volume":"7","author":[{"given":"L.","family":"Dembele","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Ang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Chavchich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2826-5225","authenticated-orcid":false,"given":"G. M. C.","family":"Bonamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. J.","family":"Selva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Yi-Xiu","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Bodenreider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. K. S.","family":"Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7951-0745","authenticated-orcid":false,"given":"F.","family":"Nosten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2333-4348","authenticated-orcid":false,"given":"B. M.","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. D.","family":"Edstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Straimer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6753-8938","authenticated-orcid":false,"given":"D. A.","family":"Fidock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. T.","family":"Diagana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Bifani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,24]]},"reference":[{"key":"2440_CR1","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1126\/science.1155165","volume":"320","author":"NJ White","year":"2008","unstructured":"White, N. J. Qinghaosu (artemisinin): the price of success. Science \n                           320, 330\u2013334 (2008).","journal-title":"Science"},{"key":"2440_CR2","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMoa0808859","volume":"361","author":"AM Dondorp","year":"2009","unstructured":"Dondorp, A. M. et al. Artemisinin resistance in Plasmodium falciparum malaria. The New England Journal of Medicine \n                           361, 455\u2013467 (2009).","journal-title":"The New England Journal of Medicine"},{"key":"2440_CR3","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1475-2875-8-10","volume":"8","author":"WO Rogers","year":"2009","unstructured":"Rogers, W. O. et al. Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia. Malaria Journal \n                           8, 10 (2009).","journal-title":"Malaria Journal"},{"key":"2440_CR4","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1128\/AAC.00686-12","volume":"57","author":"R Leang","year":"2013","unstructured":"Leang, R. et al. Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010. Antimicrobial Agents and Chemotherapy \n                           57, 818\u2013826 (2013).","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"2440_CR5","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1056\/NEJMoa1314981","volume":"371","author":"EA Ashley","year":"2014","unstructured":"Ashley, E. A. et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. The New England Journal of Medicine \n                           371, 411\u2013423 (2014).","journal-title":"The New England Journal of Medicine"},{"key":"2440_CR6","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1128\/AAC.01868-12","volume":"57","author":"B Witkowski","year":"2013","unstructured":"Witkowski, B. et al. Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia. Antimicrobial Agents and Chemotherapy \n                           57, 914\u2013923 (2013).","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"2440_CR7","unstructured":"WHO. World Malaria Report (2015). Geneva: World Health Organization WHO\/HTM\/GMP\/2015.2, 242 (2015)."},{"key":"2440_CR8","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/S1473-3099(13)70252-4","volume":"13","author":"B Witkowski","year":"2013","unstructured":"Witkowski, B. et al. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infectious Diseases \n                           13, 1043\u20131049 (2013).","journal-title":"Lancet Infectious Diseases"},{"key":"2440_CR9","doi-asserted-by":"publisher","first-page":"3157","DOI":"10.1128\/AAC.01924-13","volume":"58","author":"K Chotivanich","year":"2014","unstructured":"Chotivanich, K. et al. Laboratory detection of artemisinin-resistant Plasmodium falciparum. Antimicrobial Agents and Chemotherapy \n                           58, 3157\u20133161 (2014).","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"2440_CR10","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature12876","volume":"505","author":"F Ariey","year":"2014","unstructured":"Ariey, F. et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature \n                           505, 50\u201355 (2014).","journal-title":"Nature"},{"key":"2440_CR11","doi-asserted-by":"publisher","first-page":"e1002132","DOI":"10.1371\/journal.pbio.1002132","volume":"13","author":"C Dogovski","year":"2015","unstructured":"Dogovski, C. et al. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biology \n                           13, e1002132 (2015).","journal-title":"PLoS Biology"},{"key":"2440_CR12","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1126\/science.1260867","volume":"347","author":"J Straimer","year":"2015","unstructured":"Straimer, J. et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science \n                           347, 428\u2013431 (2015).","journal-title":"Science"},{"key":"2440_CR13","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1086\/656476","volume":"202","author":"F Teuscher","year":"2010","unstructured":"Teuscher, F. et al. Artemisinin-induced dormancy in Plasmodium falciparum: duration, recovery rates, and implications in treatment failure. Journal of Infectious Diseases \n                           202, 1362\u20131368 (2010).","journal-title":"Journal of Infectious Diseases"},{"key":"2440_CR14","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1016\/S0140-6736(84)92057-9","volume":"2","author":"GQ Li","year":"1984","unstructured":"Li, G. Q. et al. Randomised comparative study of mefloquine, qinghaosu, and pyrimethamine-sulfadoxine in patients with falciparum malaria. Lancet \n                           2, 1360\u20131361 (1984).","journal-title":"Lancet"},{"key":"2440_CR15","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1128\/AAC.01636-09","volume":"54","author":"B Witkowski","year":"2010","unstructured":"Witkowski, B. et al. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrobial Agents and Chemotherapy \n                           54, 1872\u20131877 (2010).","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"2440_CR16","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.3201\/eid2110.150682","volume":"21","author":"S Menard","year":"2015","unstructured":"Menard, S. et al. Induction of multidrug tolerance in Plasmodium falciparum by extended artemisinin pressure. Emerging Infectious Diseases \n                           21, 1733\u20131741 (2015).","journal-title":"Emerging Infectious Diseases"},{"key":"2440_CR17","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1128\/AAC.05456-11","volume":"56","author":"F Teuscher","year":"2012","unstructured":"Teuscher, F. et al. Phenotypic changes in artemisinin-resistant Plasmodium falciparum lines in vitro: evidence for decreased sensitivity to dormancy and growth inhibition. Antimicrobial Agents and Chemotherapy \n                           56, 428\u2013431 (2012).","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"2440_CR18","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1186\/1471-2164-12-391","volume":"12","author":"S Mok","year":"2011","unstructured":"Mok, S. et al. Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription. BMC Genomics \n                           12, 391 (2011).","journal-title":"BMC Genomics"},{"key":"2440_CR19","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1475-2875-10-56","volume":"10","author":"A Codd","year":"2011","unstructured":"Codd, A. et al. Artemisinin-induced parasite dormancy: a plausible mechanism for treatment failure. 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Parasitology \n                           121, 237\u2013246 (2000).","journal-title":"Parasitology"},{"key":"2440_CR22","doi-asserted-by":"publisher","first-page":"e26689","DOI":"10.1371\/journal.pone.0026689","volume":"6","author":"AN LaCrue","year":"2011","unstructured":"LaCrue, A. N. et al. Effects of artesunate on parasite recrudescence and dormancy in the rodent malaria model Plasmodium vinckei. PloS One \n                           6, e26689 (2011).","journal-title":"PloS One"},{"key":"2440_CR23","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1186\/s13059-014-0544-6","volume":"15","author":"EA Winzeler","year":"2014","unstructured":"Winzeler, E. A. & Manary, M. J. Drug resistance genomics of the antimalarial drug artemisinin. Genome Biology \n                           15, 544 (2014).","journal-title":"Genome Biology"},{"key":"2440_CR24","unstructured":"Peatey, C.L. et al. A small subset of artemisinin induced dormant P. falciparum parasites maintain mitochondrial membrane potential and resume growth in vitro. Journal of Infectious Diseases (2015)."},{"key":"2440_CR25","doi-asserted-by":"publisher","first-page":"7579","DOI":"10.1128\/AAC.02707-14","volume":"58","author":"L Grobler","year":"2014","unstructured":"Grobler, L. et al. Assessment of the induction of dormant ring stages in Plasmodium falciparum parasites by artemisone and artemisone entrapped in Pheroid vesicles in vitro. Antimicrobial Agents and Chemotherapy \n                           58, 7579\u20137582 (2014).","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"2440_CR26","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nature12782","volume":"504","author":"CW McNamara","year":"2013","unstructured":"McNamara, C. W. et al. Targeting Plasmodium PI(4)K to eliminate malaria. Nature \n                           504, 248\u2013253 (2013).","journal-title":"Nature"},{"key":"2440_CR27","doi-asserted-by":"crossref","unstructured":"Rajapakse S, Rodrigo C, Fernando SD. Tafenoquine for preventing relapse in people with Plasmodium vivax malaria. Cochrane Database Syst Rev, CD010458 (2015).","DOI":"10.1002\/14651858.CD010458.pub2"},{"key":"2440_CR28","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1038\/nrd2960","volume":"8","author":"D Mazier","year":"2009","unstructured":"Mazier, D., Renia, L. & Snounou, G. A pre-emptive strike against malaria\u2019s stealthy hepatic forms. Nature Reviews Drug discovery \n                           8, 854\u2013864 (2009).","journal-title":"Nature Reviews Drug discovery"},{"key":"2440_CR29","doi-asserted-by":"publisher","first-page":"9059","DOI":"10.1073\/pnas.0802982105","volume":"105","author":"D Plouffe","year":"2008","unstructured":"Plouffe, D. et al. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proc Natl Acad Sci USA \n                           105, 9059\u20139064 (2008).","journal-title":"Proc Natl Acad Sci USA"},{"key":"2440_CR30","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1073\/pnas.1211205110","volume":"110","author":"S Takala-Harrison","year":"2013","unstructured":"Takala-Harrison, S. et al. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci USA \n                           110, 240\u2013245 (2013).","journal-title":"Proc Natl Acad Sci USA"},{"key":"2440_CR31","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1126\/science.1215966","volume":"336","author":"IH Cheeseman","year":"2012","unstructured":"Cheeseman, I. H. et al. A major genome region underlying artemisinin resistance in malaria. Science \n                           336, 79\u201382 (2012).","journal-title":"Science"},{"key":"2440_CR32","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1016\/j.pt.2016.05.010","volume":"32","author":"L Tilley","year":"2016","unstructured":"Tilley, L. et al. Artemisinin Action and Resistance in Plasmodium falciparum. Trends Parasitol \n                           32, 682\u2013696 (2016).","journal-title":"Trends Parasitol"},{"key":"2440_CR33","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1128\/jb.155.2.768-775.1983","volume":"155","author":"HS Moyed","year":"1983","unstructured":"Moyed, H. S. & Bertrand, K. P. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. 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Nature \n                           520, 683\u2013687 (2015).","journal-title":"Nature"},{"key":"2440_CR36","doi-asserted-by":"publisher","first-page":"8713","DOI":"10.1021\/acs.jmedchem.5b01605","volume":"58","author":"C Le Manach","year":"2015","unstructured":"Le Manach, C. et al. A novel pyrazolopyridine with in vivo activity in Plasmodium berghei- and Plasmodium falciparum-infected mouse models from structure-activity relationship studies around the core of recently identified antimalarial imidazopyridazines. Journal of Medicinal Chemistry \n                           58, 8713\u20138722 (2015).","journal-title":"Journal of Medicinal Chemistry"},{"key":"2440_CR37","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/j.1365-2958.2007.05753.x","volume":"65","author":"P Hunt","year":"2007","unstructured":"Hunt, P. et al. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites. Molecular Microbiology \n                           65, 27\u201340 (2007).","journal-title":"Molecular Microbiology"},{"key":"2440_CR38","doi-asserted-by":"publisher","first-page":"3318","DOI":"10.1038\/srep03318","volume":"3","author":"S Borrmann","year":"2013","unstructured":"Borrmann, S. et al. Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya. Scientific Reports \n                           3, 3318 (2013).","journal-title":"Scientific Reports"},{"key":"2440_CR39","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1021\/ml500244m","volume":"5","author":"B Zou","year":"2014","unstructured":"Zou, B. et al. Lead optimization of imidazopyrazines: a new class of antimalarial with activity on Plasmodium liver stages. ACS Medicinal Chemistry letters \n                           5, 947\u2013950 (2014).","journal-title":"ACS Medicinal Chemistry letters"},{"key":"2440_CR40","doi-asserted-by":"publisher","first-page":"418","DOI":"10.2307\/3280287","volume":"65","author":"C Lambros","year":"1979","unstructured":"Lambros, C. & Vanderberg, J. P. Synchronization of Plasmodium falciparum erythrocytic stages in culture. Journal of Parasitology \n                           65, 418\u2013420 (1979).","journal-title":"Journal of Parasitology"},{"key":"2440_CR41","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1146\/annurev.cb.04.110188.001103","volume":"4","author":"LB Chen","year":"1988","unstructured":"Chen, L. B. Mitochondrial membrane potential in living cells. Annual Review of Cell Biology \n                           4, 155\u2013181 (1988).","journal-title":"Annual Review of Cell Biology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02440-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02440-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02440-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T23:33:48Z","timestamp":1671752028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02440-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,24]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["2440"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-02440-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,24]]},"assertion":[{"value":"3 March 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2325"}}