{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:44:37Z","timestamp":1760402677454,"version":"build-2065373602"},"reference-count":103,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sant\u00e9 publique France","award":["CNR Paludisme"],"award-info":[{"award-number":["CNR Paludisme"]}]},{"DOI":"10.13039\/501100005902","name":"D\u00e9l\u00e9gation G\u00e9n\u00e9rale pour l'Armement","doi-asserted-by":"publisher","award":["PDH-2-NRBC-4-B-4104"],"award-info":[{"award-number":["PDH-2-NRBC-4-B-4104"]}],"id":[{"id":"10.13039\/501100005902","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Half the human population is exposed to malaria. Plasmodium falciparum antimalarial drug resistance monitoring and development of new drugs are major issues related to the control of malaria. Methylene blue (MB), the oldest synthetic antimalarial, is again a promising drug after the break of its use as an antimalarial drug for more than 80 years and a potential partner for triple combination. Very few data are available on the involvement of polymorphisms on genes known to be associated with standard antimalarial drugs and parasite in vitro susceptibility to MB (cross-resistance). In this context, MB susceptibility was evaluated against 482 isolates of imported malaria from Africa by HRP2-based ELISA chemosusceptibility assay. A total of 12 genes involved in antimalarial drug resistance (Pfcrt, Pfdhfr, Pfmdr1, Pfmdr5, Pfmdr6, PfK13, Pfubq, Pfcarl, Pfugt, Pfact, Pfcoronin, and copy number of Pfpm2) were sequenced by Sanger method and quantitative PCR. On the Pfmdr1 gene, the mutation 86Y combined with 184F led to more susceptible isolates to MB (8.0 nM vs. 11.6 nM, p = 0.03). Concerning Pfmdr6, the isolates bearing 12 Asn repetitions were more susceptible to MB (4.6 nM vs. 11.6 nM, p = 0.005). None of the polymorphisms previously described as involved in antimalarial drug resistance was shown to be associated with reduced susceptibility to MB. Some genes (particularly PfK13, Pfugt, Pfact, Pfpm2) did not present enough genetic variability to draw conclusions about their involvement in reduced susceptibility to MB. None of the polymorphisms analyzed by multiple correspondence analysis (MCA) had an impact on the MB susceptibility of the samples successfully included in the analysis. It seems that there is no in vitro cross-resistance between MB and commonly used antimalarial drugs.<\/jats:p>","DOI":"10.3390\/ph14040351","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T05:52:00Z","timestamp":1618206720000},"page":"351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Absence of Association between Methylene Blue Reduced Susceptibility and Polymorphisms in 12 Genes Involved in Antimalarial Drug Resistance in African Plasmodium falciparum"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2322-5427","authenticated-orcid":false,"given":"Mathieu","family":"Gendrot","sequence":"first","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oc\u00e9ane","family":"Delandre","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Robert","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis","family":"Foguim","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Benoit","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Centre National de R\u00e9f\u00e9rence du Paludisme, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u00e9my","family":"Amalvict","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Centre National de R\u00e9f\u00e9rence du Paludisme, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Fonta","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Centre National de R\u00e9f\u00e9rence du Paludisme, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Mosnier","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Centre National de R\u00e9f\u00e9rence du Paludisme, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marylin","family":"Madamet","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Centre National de R\u00e9f\u00e9rence du Paludisme, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2360-3803","authenticated-orcid":false,"given":"Bruno","family":"Pradines","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Parasitologie et Entomologie, D\u00e9partement Microbiologie et Maladies Infectieuses, Institut de Recherche Biom\u00e9dicale des Arm\u00e9es, 13005 Marseille, France"},{"name":"Aix Marseille University, IRD, SSA, AP-HM, VITROME, 13005 Marseille, France"},{"name":"IHU M\u00e9diterran\u00e9e Infection, 13005 Marseille, France"},{"name":"Centre National de R\u00e9f\u00e9rence du Paludisme, 13005 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"on","family":"Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"ref_1","unstructured":"(2021, January 06). World Malaria Report 2020. Available online: https:\/\/www.who.int\/publications-detail-redirect\/9789240015791."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.cmi.2018.09.009","article-title":"Genetic diversity and deletion of Plasmodium falciparum Histidine-Rich Protein 2 and 3: A Threat to diagnosis of P. falciparum malaria","volume":"25","author":"Gendrot","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_3","unstructured":"(2021, January 06). World Malaria Report 2019. Available online: http:\/\/www.who.int\/malaria\/publications\/world-malaria-report-2019\/en\/."},{"key":"ref_4","unstructured":"(2021, January 06). World Health Organization WHO Status Report on Artemisinin and ACT Resistance (April 2017). Available online: http:\/\/www.who.int\/malaria\/publications\/atoz\/artemisinin-resistance-april2017\/en\/."},{"key":"ref_5","doi-asserted-by":"crossref","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":"ref_6","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1056\/NEJMoa1314981","article-title":"Spread of artemisinin resistance in Plasmodium falciparum malaria","volume":"371","author":"Ashley","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4592","DOI":"10.1128\/AAC.49.11.4592-4597.2005","article-title":"In vitro assessment of methylene blue on chloroquine-sensitive and -resistant Plasmodium falciparum strains reveals synergistic action with artemisinins","volume":"49","author":"Akoachere","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1051\/parasite\/2007142135","article-title":"Blood schizontocidal activity of methylene blue in combination with antimalarials against Plasmodium falciparum","volume":"14","author":"Garavito","year":"2007","journal-title":"Parasite"},{"key":"ref_9","first-page":"45","article-title":"In vitro antimalarial activity of methylene blue against field isolates of Plasmodium falciparum from children in southwest Nigeria","volume":"126","author":"Ademowo","year":"2007","journal-title":"Indian J. Med. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1128\/AAC.01466-10","article-title":"In vitro activity of Proveblue (methylene blue) on Plasmodium falciparum strains resistant to standard antimalarial drugs","volume":"55","author":"Pascual","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12936-015-0589-3","article-title":"Plasmodium falciparum susceptibility to standard and potential anti-malarial drugs in Dakar, Senegal, during the 2013\u20132014 malaria season","volume":"14","author":"Fall","year":"2015","journal-title":"Malar. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ijantimicag.2017.03.019","article-title":"Ex vivo activity of Proveblue, a methylene blue, against field isolates of Plasmodium falciparum in Dakar, Senegal from 2013\u20132015","volume":"50","author":"Fall","year":"2017","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_13","first-page":"2141","article-title":"Baseline and multinormal distribution of ex vivo susceptibilities of Plasmodium falciparum to methylene blue in Africa, 2013-18","volume":"75","author":"Gendrot","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/jac\/dku326","article-title":"Methylene blue inhibits the asexual development of vivax malaria parasites from a region of increasing chloroquine resistance","volume":"70","author":"Suwanarusk","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6117","DOI":"10.1128\/AAC.00874-15","article-title":"Potent ex vivo activity of naphthoquine and methylene blue against drug-resistant clinical isolates of Plasmodium falciparum and Plasmodium vivax","volume":"59","author":"Wirjanata","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1128\/AAC.06073-11","article-title":"Proveblue (methylene blue) as an antimalarial agent: In vitro synergy with dihydroartemisinin and atorvastatin","volume":"56","author":"Dormoi","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4080","DOI":"10.1128\/AAC.00634-13","article-title":"Dose responses of Proveblue methylene blue in an experimental murine cerebral malaria model","volume":"57","author":"Dormoi","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3412","DOI":"10.1128\/AAC.02381-12","article-title":"Efficacy of Proveblue (methylene blue) in an experimental cerebral malaria murine model","volume":"57","author":"Dormoi","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/1475-2875-12-127","article-title":"Impact of methylene blue and atorvastatin combination therapy on the apparition of cerebral malaria in a murine model","volume":"12","author":"Dormoi","year":"2013","journal-title":"Malar. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E1214","DOI":"10.1073\/pnas.1112037108","article-title":"Quantitative assessment of plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue","volume":"108","author":"Adjalley","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3268","DOI":"10.1128\/AAC.00325-13","article-title":"Male and female Plasmodium falciparum mature gametocytes show different responses to antimalarial drugs","volume":"57","author":"Delves","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12936-017-2153-9","article-title":"Methylene blue induced morphological deformations in Plasmodium falciparum gametocytes: Implications for transmission-blocking","volume":"17","author":"Wadi","year":"2018","journal-title":"Malar. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s12936-018-2300-y","article-title":"Differential activity of methylene blue against erythrocytic and hepatic stages of Plasmodium","volume":"17","author":"Franetich","year":"2018","journal-title":"Malar. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1093\/cid\/ciz134","article-title":"Transmission-blocking effects of primaquine and methylene blue suggest Plasmodium falciparum gametocyte sterilization rather than effects on sex ratio","volume":"69","author":"Bradley","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1093\/infdis\/jiu540","article-title":"Efficacy and safety of triple combination therapy with artesunate-amodiaquine-methylene blue for falciparum malaria in children: A randomized controlled trial in Burkina Faso","volume":"211","author":"Coulibaly","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S1473-3099(18)30044-6","article-title":"Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: A phase 2, single-blind, randomised controlled trial","volume":"18","author":"Dicko","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1128\/AAC.02248-12","article-title":"The Antimalarial activities of methylene blue and the 1,4-naphthoquinone 3-[4-(trifluoromethyl)benzyl]-menadione are not due to inhibition of the mitochondrial electron transport chain","volume":"57","author":"Ehrhardt","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1089\/ars.2011.4239","article-title":"Interactions of the antimalarial drug methylene blue with methemoglobin and heme targets in Plasmodium falciparum: A physico-biochemical study","volume":"17","author":"Blank","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nsmb.3216","article-title":"Mechanistic diversity in ATP-binding cassette (ABC) transporters","volume":"23","author":"Locher","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1042\/BST20150139","article-title":"ABC transporter research: Going strong 40 years on","volume":"43","author":"Theodoulou","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_31","unstructured":"Ponte-Sucre, A. (2009). ABC transporters in Plasmodium falciparum and their involvement in resistance to antimalarial drugs. ABC Transporters in Microorganisms: Research, Innovation and Value as Targets against Drug Resistance, Caister Academic Press."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1126\/science.2658061","article-title":"Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum","volume":"244","author":"Wilson","year":"1989","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/345255a0","article-title":"Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum","volume":"345","author":"Foote","year":"1990","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/35002615","article-title":"Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum","volume":"403","author":"Reed","year":"2000","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0166-6851(00)00201-2","article-title":"The Tyrosine-86 allele of the Pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin","volume":"108","author":"Duraisingh","year":"2000","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.actatropica.2019.05.020","article-title":"Modulation of in vitro antimalarial responses by polymorphisms in Plasmodium falciparum ABC transporters (Pfmdr1 and Pfmdr5)","volume":"196","author":"Gendrot","year":"2019","journal-title":"Acta Trop."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7032","DOI":"10.1128\/AAC.03494-14","article-title":"Role of Pfmdr1 in in vitro Plasmodium falciparum susceptibility to chloroquine, quinine, monodesethylamodiaquine, mefloquine, lumefantrine, and dihydroartemisinin","volume":"58","author":"Wurtz","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/1475-2875-8-205","article-title":"Localization of the ATP-binding cassette (ABC) transport proteins PfMRP1, PfMRP2, and PfMDR5 at the Plasmodium falciparum plasma membrane","volume":"8","author":"Kavishe","year":"2009","journal-title":"Malar. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6196","DOI":"10.1128\/AAC.01465-13","article-title":"Repeat Polymorphisms in the low-complexity regions of Plasmodium falciparum ABC transporters and associations with in vitro antimalarial responses","volume":"57","author":"Okombo","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s12936-015-0581-y","article-title":"PfMDR2 and PfMDR5 are dispensable for Plasmodium falciparum asexual parasite multiplication but change in vitro susceptibility to anti-malarial drugs","volume":"14","author":"Rijpma","year":"2015","journal-title":"Malar. J."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, Z., Parker, D., Meng, H., Wu, L., Li, J., Zhao, Z., Zhang, R., Miao, M., Fan, Q., and Wang, H. (2012). In vitro sensitivity of Plasmodium falciparum from China-Myanmar border area to major act drugs and polymorphisms in potential target genes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030927"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e01183-16","DOI":"10.1128\/AAC.01183-16","article-title":"Association between polymorphisms in the Pfmdr6 Gene and ex vivo susceptibility to quinine in Plasmodium falciparum parasites from Dakar, Senegal","volume":"61","author":"Gendrot","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1093\/molbev\/msh205","article-title":"The malaria parasite\u2019s chloroquine resistance transporter is a member of the drug\/metabolite transporter superfamily","volume":"21","author":"Martin","year":"2004","journal-title":"Mol. Biol. Evol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1126\/science.1074045","article-title":"Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by Pfcrt mutations","volume":"298","author":"Sidhu","year":"2002","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1128\/AAC.47.1.87-94.2003","article-title":"Pfcrt polymorphism and chloroquine resistance in Plasmodium falciparum strains isolated in Cambodia","volume":"47","author":"Lim","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_46","first-page":"59","article-title":"Implications des pompes membranaires de Plasmodium falciparum dans le transport et la r\u00e9sistance aux antipaludiques","volume":"2020","author":"Pradines","year":"2020","journal-title":"Rev. Francoph. Lab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A Molecular marker of artemisinin-resistant Plasmodium falciparum malaria","volume":"505","author":"Ariey","year":"2014","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1056\/NEJMoa1513137","article-title":"A worldwide map of Plasmodium falciparum K13-propeller polymorphisms","volume":"374","author":"Khim","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1186\/s12936-019-2916-6","article-title":"Are K13 and Plasmepsin II genes, involved in Plasmodium falciparum resistance to artemisinin derivatives and piperaquine in Southeast Asia, reliable to monitor resistance surveillance in Africa?","volume":"18","author":"Tsombeng","year":"2019","journal-title":"Malar. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1038\/s41591-020-1005-2","article-title":"Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum Kelch13 R561H mutant Parasites in Rwanda","volume":"26","author":"Uwimana","year":"2020","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","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":"ref_52","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1093\/jac\/dkz098","article-title":"Plasmodium falciparum K13 expression associated with parasite clearance during artemisinin-based combination therapy","volume":"7","author":"Silva","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/S1473-3099(16)30415-7","article-title":"A Surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: A phenotype-genotype association study","volume":"17","author":"Witkowski","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S1473-3099(16)30409-1","article-title":"Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: A genotype-phenotype association study","volume":"17","author":"Amato","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1128\/AAC.05618-11","article-title":"The F423Y mutation in the Pfmdr2 gene and mutations N51I, C59R, and S108N in the Pfdhfr gene are independently associated with pyrimethamine resistance in Plasmodium falciparum isolates","volume":"56","author":"Briolant","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"350","DOI":"10.4269\/ajtmh.2003.68.350","article-title":"Analysis of Pfcrt, Pfmdr1, Dhfr, and Dhps Mutations and drug sensitivities in Plasmodium falciparum isolates from patients in Vietnam before and after treatment with artemisinin","volume":"68","author":"Ngo","year":"2003","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev.biochem.67.1.425","article-title":"The ubiquitin system","volume":"67","author":"Hershko","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1039\/C3MB70506D","article-title":"The ubiquitin system: An essential component to unlocking the secrets of malaria parasite biology","volume":"10","author":"Hamilton","year":"2014","journal-title":"Mol. Biosyst."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"13052","DOI":"10.1073\/pnas.1210585109","article-title":"Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite","volume":"109","author":"Park","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Sanchez, C.P., Liu, C.-H., Mayer, S., Nurhasanah, A., Cyrklaff, M., Mu, J., Ferdig, M.T., Stein, W.D., and Lanzer, M. (2014). A HECT ubiquitin-Protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004382"},{"key":"ref_61","unstructured":"Ribacke, U., Bartlett, M., Patel, S.D., Seneratne, N., Park, D.J., Duraisingh, M., Sabeti, P.C., Volkman, S.K., and Wirth, D.F. (2012, January 11\u201315). Adaptative evolution of a ring ubiquitin ligase mediates reduced drug sensitivity in Plasmodium falciparum. Proceedings of the 61st Meeting of American Society of Tropical Medicine and Hygiene, Atlanta, GA, USA."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5010","DOI":"10.1128\/AAC.03105-15","article-title":"Absence of association between polymorphisms in the RING E3 ubiquitin protein ligase gene and ex vivo susceptibility to conventional antimalarial drugs in Plasmodium falciparum isolates from Dakar, Senegal","volume":"60","author":"Gendrot","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"12799","DOI":"10.1073\/pnas.1812317115","article-title":"Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility","volume":"115","author":"Demas","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1186\/s12936-015-0801-5","article-title":"Plasmodium falciparum coronin organizes arrays of parallel actin filaments potentially guiding directional motility in invasive malaria parasites","volume":"14","author":"Olshina","year":"2015","journal-title":"Malar. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0014-5793(98)01557-9","article-title":"A Plasmodium falciparum novel gene encoding a coronin-like protein which associates with actin filaments","volume":"441","author":"Tardieux","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Sharma, A.I., Shin, S.H., Bopp, S., Volkman, S.K., Hartl, D.L., and Wirth, D.F. (2020). Genetic background and PfKelch13 affect artemisinin susceptibility of PfCoronin mutants in Plasmodium falciparum. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1009266"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"106190","DOI":"10.1016\/j.ijantimicag.2020.106190","article-title":"Absence of association between polymorphisms in the Pfcoronin and Pfk13 genes and the presence of Plasmodium falciparum parasites after treatment with artemisinin derivatives in Senegal","volume":"56","author":"Delandre","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"R26","DOI":"10.1186\/gb-2005-6-3-r26","article-title":"The \u201cpermeome\u201d of the malaria parasite: An overview of the membrane transport proteins of Plasmodium falciparum","volume":"6","author":"Martin","year":"2005","journal-title":"Genome Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"16166","DOI":"10.1038\/nmicrobiol.2016.166","article-title":"UDP-Galactose and Acetyl-CoA transporters as Plasmodium multidrug resistance genes","volume":"1","author":"Lim","year":"2016","journal-title":"Nat. Microbiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5060","DOI":"10.1128\/AAC.02727-13","article-title":"KAF156 Is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission","volume":"58","author":"Kuhen","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e00696-16","DOI":"10.1128\/mBio.00696-16","article-title":"Mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) confer multidrug resistance","volume":"7","author":"LaMonte","year":"2016","journal-title":"MBio"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1021\/acsinfecdis.6b00025","article-title":"Plasmodium falciparum cyclic amine resistance locus (PfCARL), a resistance mechanism for two distinct compound classes","volume":"2","author":"Magistrado","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1126\/science.1167983","article-title":"Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum","volume":"323","author":"Jonikas","year":"2009","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-019-2919-3","article-title":"Low polymorphisms in Pfact, Pfugt and Pfcarl genes in African Plasmodium falciparum isolates and absence of association with susceptibility to common anti-malarial drugs","volume":"18","author":"Foguim","year":"2019","journal-title":"Malar. J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/00034983.1997.11813174","article-title":"Haematin (haem) polymerization and its inhibition by quinoline antimalarials","volume":"91","author":"Ridley","year":"1997","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"ref_76","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":"Fidock","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1056\/NEJM200101253440403","article-title":"A molecular marker for chloroquine-resistant falciparum malaria","volume":"344","author":"Doumbo","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_78","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":"Veiga","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1086\/427997","article-title":"In vivo selection of Plasmodiumf falciparum Pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem)","volume":"191","author":"Sisowath","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1128\/AAC.50.5.1893-1895.2006","article-title":"Selection of Plasmodium falciparum Pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic","volume":"50","author":"Dokomajilar","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/S0140-6736(04)16767-6","article-title":"Mefloquine resistance in Plasmodium falciparum and increased Pfmdr1 gene copy number","volume":"364","author":"Price","year":"2004","journal-title":"Lancet"},{"key":"ref_82","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":"Venkatesan","year":"2014","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_83","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":"Conrad","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5649","DOI":"10.1128\/AAC.00920-16","article-title":"Intermittent preventive treatment with dihydroartemisinin-piperaquine in Ugandan schoolchildren selects for Plasmodium falciparum transporter polymorphisms that modify drug sensitivity","volume":"60","author":"Nankabirwa","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.meegid.2005.09.001","article-title":"Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of Pfcrt 76T and Pfmdr1 86Y","volume":"6","author":"Holmgren","year":"2006","journal-title":"Infect. Genet. Evol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.meegid.2007.03.005","article-title":"Selection of Pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa","volume":"7","author":"Holmgren","year":"2007","journal-title":"Infect. Genet. Evol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.actatropica.2009.12.008","article-title":"Selection of Pfmdr1 and Pfcrt alleles in amodiaquine treatment failure in North-Western Burkina Faso","volume":"114","author":"Danquah","year":"2010","journal-title":"Acta Trop."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1093\/infdis\/jiv551","article-title":"Artesunate\/Amodiaquine versus Artemether\/Lumefantrine for the treatment of uncomplicated malaria in Uganda: A randomized trial","volume":"213","author":"Yeka","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/1475-2875-8-89","article-title":"A Systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria","volume":"8","author":"Picot","year":"2009","journal-title":"Malar. J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1186\/1475-2875-12-414","article-title":"PftetQ and Pfmdt copy numbers as predictive molecular markers of decreased ex vivo doxycycline susceptibility in imported Plasmodium falciparum malaria","volume":"12","author":"Gaillard","year":"2013","journal-title":"Malar. J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s12936-018-2252-2","article-title":"The D113N mutation in the RING E3 ubiquitin protein ligase gene is not associated with ex vivo susceptibility to common anti-malarial drugs in African Plasmodium falciparum isolates","volume":"17","author":"Gendrot","year":"2018","journal-title":"Malar. J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"953","DOI":"10.4269\/ajtmh.2006.74.953","article-title":"Genetic diversity and structure of African Plasmodium falciparum populations in urban and rural areas","volume":"74","author":"Bogreau","year":"2006","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"146","DOI":"10.4269\/ajtmh.2006.75.146","article-title":"Urban malaria in Dakar, Senegal: Chemosusceptibility and genetic diversity of Plasmodium falciparum isolates","volume":"75","author":"Henry","year":"2006","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-020-03281-x","article-title":"Prevalence of mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, and association with ex vivo susceptibility to common anti-malarial drugs against African Plasmodium falciparum isolates","volume":"19","author":"Foguim","year":"2020","journal-title":"Malar. J."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1186\/1475-2875-13-472","article-title":"Limited polymorphisms in K13 Gene in Plasmodium falciparum isolates from Dakar, Senegal in 2012\u20132013","volume":"13","author":"Fall","year":"2014","journal-title":"Malar. J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e00374-18","DOI":"10.1128\/AAC.00374-18","article-title":"Absence of a high level of duplication of the Plasmepsin II gene in Africa","volume":"62","author":"Robert","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e02445-18","DOI":"10.1128\/AAC.02445-18","article-title":"Baseline ex vivo and molecular responses of Plasmodium falciparum isolates to piperaquine before implementation of dihydroartemisinin-piperaquine in Senegal","volume":"63","author":"Robert","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_98","first-page":"1","article-title":"FactoMineR: An R Package for Multivariate Analysis","volume":"25","author":"Josse","year":"2008","journal-title":"J. Stat. Softw."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3615","DOI":"10.1128\/AAC.06350-11","article-title":"Pfmdr1 amplification is related to increased Plasmodium falciparum in vitro sensitivity to the bisquinoleine piperaquine","volume":"56","author":"Veiga","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7687","DOI":"10.1074\/jbc.M806944200","article-title":"Disruption of a Plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione","volume":"284","author":"Raj","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_101","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":"Imwong","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e01441-19","DOI":"10.1128\/AAC.01441-19","article-title":"Pharmacokinetics and ex vivo antimalarial ativity of artesunate-amodiaquine plus methylene blue in healthy volunteers","volume":"64","author":"Ahn","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Jorge, M.M., Ouermi, L., Meissner, P., Compaor\u00e9, G., Coulibaly, B., Nebie, E., Krisam, J., Klose, C., Kieser, M., and Jahn, A. (2019). Safety and efficacy of artesunate-amodiaquine combined with either methylene blue or primaquine in children with falciparum malaria in Burkiba Faso: A randomized controlled trial. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0222993"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/4\/351\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:59:18Z","timestamp":1760363958000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/4\/351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":103,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ph14040351"],"URL":"https:\/\/doi.org\/10.3390\/ph14040351","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2021,4,9]]}}}