Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

Antimicrobial Agents and Chemotherapy

Volumn 58, Issue 12, 2014, Pages 7032-7040

  Wurtz, Nathalie ^a,b   Fall, Bécaye ^c   Pascual, Aurélie ^a,b,d   Fall, Mansour ^c   Baret, Eric ^a,b,c,d   Camara, Cheikhou ^c   Nakoulima, Aminata ^c   Diatta, Bakary ^c   Fall, Khadidiatou Ba ^c   Mbaye, Pape Saliou ^c   Diémé, Yaya ^c   Bercion, Raymond ^c,e   Wade, Boubacar ^c   Pradines, Bruno ^a,b,c,d  

^a INSTITUT DE RECHERCHE BIOMÉDICALE DES ARMÉES   (France)

^b AIX MARSEILLE UNIVERSITÉ   (France)

^c HÔPITAL PRINCIPAL DE DAKAR   (Senegal)

^d Centre National de Reference du Paludisme   (France)

^e INSTITUT PASTEUR DE DAKAR   (Senegal)

Author keywords

[No Author keywords available]

Indexed keywords

ASPARAGINE; ASPARTIC ACID; BENFLUMETOL; CHLOROQUINE; CYSTEINE; DEETHYLAMODIAQUINE; DIHYDROARTEMISININ; MEFLOQUINE; MULTIDRUG RESISTANCE PROTEIN; PFMDR1 PROTEIN; PHENYLALANINE; QUININE; SERINE; TYROSINE; UNCLASSIFIED DRUG; AMODIAQUINE; ANTIMALARIAL AGENT; ARTEMISININ DERIVATIVE; ETHANOLAMINE DERIVATIVE; FLUORENE DERIVATIVE; MDR1 PROTEIN, PLASMODIUM FALCIPARUM;

AMINO ACID SUBSTITUTION; ANTIMALARIAL DRUG RESISTANCE; ANTIMALARIAL DRUG SUSCEPTIBILITY; ARTICLE; CONTROLLED STUDY; ERYTHROCYTE; EX VIVO STUDY; GENE MUTATION; GENETIC ASSOCIATION; HAPLOTYPE; HUMAN; HUMAN CELL; IC50; IN VITRO STUDY; PARASITE ISOLATION; PLASMODIUM FALCIPARUM; SINGLE NUCLEOTIDE POLYMORPHISM; WILD TYPE; ADULT; ANALOGS AND DERIVATIVES; CHILD; DRUG EFFECTS; DRUG RESISTANCE; DRUG SENSITIVITY; FEMALE; GENE EXPRESSION; GENETICS; GROWTH, DEVELOPMENT AND AGING; MALARIA, FALCIPARUM; MALE; METABOLISM; PARASITOLOGY; SENEGAL; TRANSPORT AT THE CELLULAR LEVEL;

ADULT; AMODIAQUINE; ANTIMALARIALS; ARTEMISININS; BIOLOGICAL TRANSPORT; CHILD; CHLOROQUINE; DRUG RESISTANCE; ERYTHROCYTES; ETHANOLAMINES; FEMALE; FLUORENES; GENE EXPRESSION; HAPLOTYPES; HUMANS; INHIBITORY CONCENTRATION 50; MALARIA, FALCIPARUM; MALE; MEFLOQUINE; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; PARASITIC SENSITIVITY TESTS; PLASMODIUM FALCIPARUM; POLYMORPHISM, SINGLE NUCLEOTIDE; QUININE; SENEGAL;

EID: 84912573317     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.03494-14     Document Type: Article

References (67)

1. Ndiaye JLA, Faye B, Gueye A, Tine R, Ndiaye D, Tchania C, Ndiaye I, Barry A, Cisse B, Lameyre V, Gaye O. 2011. Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial. Malar. J. 10:237. http://dx .doi.org/10.1186/1475-2875-10-237.
2. Thiam S, Thior M, Faye B, Diouf ML, Diouf MB, Diallo I, Fall FB, Ndiaye JL, Albertini A, Lee E, Jorgensen P, Gaye O, Bell D. 2011. Major reduction in anti-malarial drug consumption in Senegal after nation-wide introduction of malaria rapid diagnostic tests. PLoS One 6:18419. http: //dx.doi.org/10.1371/journal.pone.0018419.
3. Basco LK, Ringwald P. 1998. Molecular epidemiology of malaria in Yaoundé, Cameroon. III. Analysis of chloroquine resistance and point mutations in the multidrug resistance 1 (pfmdr 1) gene of Plasmodium falciparum. Am. J. Trop. Med. Hyg. 59:577-581.
4. Duraisingh MT, Drakeley CJ, Muller O, Bailey R, Snounou G, Targett GA, Greenwood BM, Warhurst DC. 1997. Evidence for selection for the tyrosine-86 allele of the pfmdr 1 gene of Plasmodium falciparum by chloroquine and amodiaquine. Parasitology 114:205-211. http://dx.doi.org /10.1017/S0031182096008487.
5. Foote SJ, Kyle DE, Martin RK, Oduola AM, Forsyth K, Kemp DJ, Cowman AF. 1990. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance. Nature 345:255-258. http://dx .doi.org/10.1038/345255a0.
6. Grobusch MP, Adagu IS, Kremsner PG, Warhurst DC. 1998. Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon. Parasitology 116:211-217. http://dx.doi.org/10.1017/S0031182097002266.
7. Picot S, Olliaro P, de Monbrison F, Bienvenu AL, Price RN, Ringwald P. 2009. A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malar. J. 8:89. http://dx.doi.org/10.1186/1475-2875 -8-89.
8. Marfurt J, Muller I, Sie A, Oa O, Reeder JC, Smith TA, Beck HP, Genton B. 2008. The usefulness of twenty-four molecular markers in predicting treatment outcome with combination therapy of amodiaquine plus sulphadoxine-pyrimethamine against falciparum malaria in Papua New Guinea. Malar. J. 7:61. http://dx.doi.org/10.1186/1475-2875-7-61.
9. Ruetz S, Delling U, Brault M, Schurr E, Gros P. 1996. The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells. Proc. Natl. Acad. Sci. U. S. A. 93:9942-9947. http://dx.doi .org/10.1073/pnas.93.18.9942.
10. Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF. 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403:906-909. http://dx.doi.org/10.1038/35002615.
11. Pillai DR, Hijar G, Montoya I, Marquino W, Ruebush TK, Wrongsrichanalai C, Kain KC. 2003. Lack of prediction of mefloquine and mefloquine-artesunate treatment outcome by mutations in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene for P. falciparum malaria in Peru. Am. J. Trop. Med. Hyg. 68:107-110.
12. Price RN, Cassar C, Brockman A, Duraisingh M, van Vugt M, White NJ, Nosten F, Krishna S. 1999. The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrob. Agents Chemother. 43:2943-2949.
13. Duraisingh MT, Jones P, Sambou I, von Seidlein L, Pinder M, Warhurst DC. 2000. The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Mol. Biochem. Parasitol. 108:13-23. http: //dx.doi.org/10.1016/S0166-6851(00)00201-2.
14. Duraisingh MT, Roper C, Walliker D, Warhurst DC. 2000. Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum. Mol. Microbiol. 36:955-961. http://dx.doi.org/10.1046/j.1365-2958.2000.01914.x.
15. Baliraine FN, Rosenthal PJ. 2011. Prolonged selection of pfmdr1 polymorphisms after treatment of falciparum malaria with artemetherlumefantrine in Uganda. J. Infect. Dis. 204:1120-1124. http://dx.doi.org /10.1093/infdis/jir486.
16. Lekana-Douki JB, Dinzouna Boutamba SD, Zatra R, Zang Edou SE, Ekomy H, Bisvigou U, Toure-Ndouo FS. 2011. Increased prevalence of the Plasmodium falciparum Pfmdr1 86N genotype among field isolates from Franceville, Gabon after replacement of chloroquine by artemetherlumefantrine and artesunate-mefloquine. Infect. Genet. Evol. 11:512-517. http://dx.doi.org/10.1016/j.meegid.2011.01.003.
17. Mwai L, Kiara SM, Abdirahman A, Pole L, Rippert A, Diriye A, Bull Marsh PK, Borrmann S, Nzila A. 2009. In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1. Antimicrob. Agents Chemother. 53:5069-5073. http://dx.doi.org/10.1128/AAC.00638-09.
18. Ngo T, Duraisingh M, Reed M, Hipgrave D, Biggs B, Cowman AF. 2003. 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. Am. J. Trop. Med. Hyg. 68:350-356.
19. Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LMB, Sidhu ABS, Naudé B, Deitsch KW, Su XZ, Wootton JC, Roepe PD, Wellems TE. 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6:861-871. http://dx.doi.org/10.1016 /S1097-2765(05)00077-8.
20. Nagesha HS, Casey GJ, Rieckmann H, Fryauff DJ, Laksana BS, Reeder JC, Maguire JD, Baird J. 2003. New haplotypes of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene among chloroquine- resistant parasite isolates. Am. J. Trop. Med. Hyg. 68:398-402.
21. Johnson DJ, Fidock DA, Mungthin M, Lakshmanan V, Sidhu AB, Bray PG, Ward SA. 2004. Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol. Cell 15:867-877. http://dx.doi.org/10.1016/j.molcel.2004.09.012.
22. Baro NK, Callaghan PS, Roepe PD. 2013. Function of resistance conferring Plasmodium falciparum chloroquine resistance transporter isoforms. Biochemistry 52:4242-4249. http://dx.doi.org/10.1021/bi400557x.
23. Fall B, Diawara S, Sow K, Baret E, Diatta B, Fall KB, Mbate PS, Fall F, Diémé Y, Rogier C, Wade B, Bercion R, Pradines B. 2011. Ex vivo susceptibility of Plasmodium isolates from Dakar, Senegal, to seven standard anti-malarial drugs. Malar. J. 10:310. http://dx.doi.org/10.1186/1475 -2875-10-310.
24. Wurtz N, Fall B, Pascual A, Diawara S, Sow K, Baret E, Diatta B, Fall KB, Mbaye PS, Fall F, Diémé Y, Rogier C, Bercion R, Briolant S, Wade B, Pradines B. 2012. Prevalence of molecular markers of Plasmodium falciparum drug resistance in Dakar, Senegal. Malar. J. 11:197. http://dx .doi.org/10.1186/1475-2875-11-197.
25. Lambros C, Vanderberg JP. 1979. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J. Parasitol. 65:418-420. http://dx .doi.org/10.2307/3280287.
26. Bogreau H, Renaud F, Bouchiba H, Durand P, Assi SB, Henry MC, Garnotel E, Pradines B, Fusai T, Wade B, Adehossi E, Parola P, Kamil MO, Puijalon O, Rogier C. 2006. Genetic diversity and structure of African Plasmodium falciparum populations in urban and rural areas. Am. J. Trop. Med. Hyg. 74:953-959.
27. Henry M, Diallo I, Bordes J, Ka S, Pradines B, Diatta B, M'Baye PS, Sane M, Thiam M, Gueye PM, Wade B, Touze JE, Debonne JM, Rogier C, Fusai T. 2006. Urban malaria in Dakar, Senegal: chemosusceptibility and genetic diversity of Plasmodium falciparum isolates. Am. J. Trop. Med. Hyg. 75:146-151.
28. Pascual A, Basco LK, Baret E, Amalvict R, Travers D, Rogier C, Pradines B. 2011. Use of the atmospheric generators for capnophilic bacteria Genbag CO2 for the evaluation of in vitro Plasmodium falciparum susceptibility to standard anti-malarial drugs. Malar. J. 10:8. http://dx.doi .org/10.1186/1475-2875-10-8.
29. Kaddouri H, Nakache S, Houzé S, Mentré F, Le Bras J. 2006. Assessment of the drug susceptibility of Plasmodium falciparum clinical isolates from Africa using a Plasmodium lactate dehydrogenase immunodetection assay and an inhibitory maximum effect model for precise measurement of the 50-percent inhibitory concentration. Antimicrob. Agents Chemother. 50: 3343-3349. http://dx.doi.org/10.1128/AAC.00367-06.
30. Le Nagard H, Vincent C, Mentré F, Le Bras J. 2011. Online analysis of in vitro resistance to antimalarial drugs through nonlinear regression. Comput. Methods Programs Biomed. 104:10-18. http://dx.doi.org/10 .1016/j.cmpb.2010.08.003.
31. Basco LK, Ringwald P. 2002. Molecular epidemiology of malaria in Cameroon. X. Evaluation of Pfmdr1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives. Am. J. Trop. Med. Hyg. 66:667-671.
32. Tinto H, Ouédraogo JB, Erhart A, van Overmeir C, Dujardin JC, van Marck E, Guiguemdé TR, D'Alessandro U. 2003. Relationship between the Pfcrt T76 and the Pfmdr-1 Y86 mutations in Plasmodium falciparum and in vitro/in vivo chloroquine resistance in Burkina Faso, West Africa. Infect. Genet. Evol. 3:287-292. http://dx.doi.org/10.1016/j.meegid.2003 .08.002.
33. Sibley CH, Barnes KI, Watkins WM, Plowe CV. 2008. A network to monitor antimalarial drug resistance: a plan for moving forward. Trends Parasitol. 24:43-48. http://dx.doi.org/10.1016/j.pt.2007.09.008.
34. Sibley CH, Barnes KI, Plowe CV. 2007. The rationale and plan for creating a World Antimalarial Resistance Network (WARN). Malar. J. 6:118. http://dx.doi.org/10.1186/1475-2875-6-118.
35. Plowe CV, Roper C, Barnwell JW, Happi CT, Joshi HH, Mbacham W, Meshnick SR, Mugittu K, Naidoo I, Price RN, Shafer RW, Sibley CH, Sutherland CJ, Zimmerman PA, Rosenthal PJ. 2007. World Antimalarial Resistance Network (WARN) III: molecular markers for drug resistant malaria. Malar. J. 6:121. http://dx.doi.org/10.1186/1475-2875-6-121.
36. Holmgren G, Gil JP, Ferreira PM, Veiga MI, Obonyo CO, Bjorkman A. 2006. Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infect. Genet. Evol. 6:309-314. http://dx.doi.org/10.1016/j.meegid.2005.09.001.
37. Sa JM, Twu O, Hayton K, Reyes S, Fay MP, Ringwald P, Wellems TE. 2009. Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. Proc. Natl. Acad. Sci. U. S. A. 106:18883-18889. http://dx.doi.org/10.1073 /pnas.0911317106.
38. Sidhu AB, Valderramos SG, Fidock DA. 2005. Pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum. Mol. Microbiol. 57:913-926. http: //dx.doi.org/10.1111/j.1365-2958.2005.04729.x.
39. Sisowath C, Ferreira PE, Bustamante LY, Dahlstrom S, Martensson A, Bjorkman A, Krishna Gil JP. 2007. The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Trop. Med. Int. Health 12:736-742. http://dx.doi.org/10.1111/j.1365-3156.2007.01843.x.
40. Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, Björkman A, Gil JP. 2005. In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). J. Infect. Dis. 191:1014-1017. http://dx.doi.org/10.1086/427997.
41. Pickard AL, Wongsrichanalai C, Purfield A, Kamwendo D, Emery K, Zalewsky C, Kamwendo F, Miller RS, Meshnick SR. 2003. Resistance to anti-malarials in Southeast Asia and genetic polymorphisms in pfmdr1. Antimicrob. Agents Chemother. 47:2418-2423. http://dx.doi.org/10 .1128/AAC.47.8.2418-2423.2003.
42. Phompradit P, Wisedpanichkij R, Muhamad P, Chaijaroenkul W, Na-Bangchang K. 2011. Molecular analysis of pfatp6 and pfmdr1 polymorphisms and their association with in vitro sensitivity in Plasmodium falciparum isolates from the Thai-Myanmar border. Acta Trop. 120:130 -135. http://dx.doi.org/10.1016/j.actatropica.2011.07.003.
43. Dahlström S, Aubouy A, Maïga-Ascofaré O, Faucher JF, Wakpo A, Ezinmègnon S, Massougbodji A, Houzé P, Kendjo E, Deloron P, Le Bras J, Houzé S. 2014. Plasmodium falciparum polymorphism associated with ex vivo drug susceptibility and clinical effectiveness of artemisininbased combination therapies in Benin. Antimicrob. Agents Chemother. 58:1-10. http://dx.doi.org/10.1128/AAC.01790-12.
44. Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, Patel R, Laing K, Looareesuwan S, White NJ, Nosten F, Krishna S. 2004. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364:438-447. http://dx.doi.org/10 .1016/S0140-6736(04)16767-6.
45. Mungthin M, Khositnithikul R, Sitthichot N, Suwandittakul N, Wattanaveeradej V, Ward SA, Na-Bangchang K. 2010. Association between the pfmdr1 gene and in vitro artemether and lumefantrine sensitivity in Thai isolates of Plasmodium falciparum. Am. J. Trop. Med. Hyg. 83:1005-1009. http://dx.doi.org/10.4269/ajtmh.2010.10-0339.
46. Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Björkman A. 2005. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin. Infect. Dis. 41:1079-1086. http://dx.doi.org/10 .1086/444460.
47. Dokomajilar C, Nsobya SL, Greenhouse B, Rosenthal PJ, Dorsey G. 2006. Selection of Plasmodium falciparum pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrob. Agents Chemother. 50:1893-1895. http://dx .doi.org/10.1128/AAC.50.5.1893-1895.2006.
48. Folarin OA, Bustamante C, Gbotosho GO, Sowunmi A, Zalis MG, Oduola AMJ, Happi CT. 2011. In vitro amodiaquine resistance and its association with mutations in pfcrt and pfmdr1 genes of Plasmodium falciparum isolates from Nigeria. Acta Trop. 120:224-230. http://dx.doi.org /10.1016/j.actatropica.2011.08.013.
49. Danquah I, Coulibaly B, Meissner P, Petruschke I, Muller O, Mockenhaupt FP. 2010. Selection of pfmdr1 and pfcrt alleles in amodiaquine treatment failure in north-western Burkina Faso. Acta Trop. 114:63-73. http://dx.doi.org/10.1016/j.actatropica.2009.12.008.
50. Nsobya SL, Dokomajilar C, Joloba M, Dorsey G, Rosenthal PJ. 2007. Resistance mediating Plasmodium falciparum pfcrt and pfmdr1 alleles after treatment with artesunate-amodiaquine in Uganda. Antimicrob. Agents Chemother. 51:3023-3025. http://dx.doi.org/10.1128/AAC.00012-07.
51. Echeverry DF, Holmgren G, Murillo C, Higuita JC, Gil JP, Osorio L. 2007. Polymorphisms in the pfcrt and pfmdr1 genes of Plasmodium falciparum and in vitro susceptibility to amodiaquine and desethylamodiaquine. Am. J. Trop. Med. Hyg. 77:1034-1038.
52. Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P, Kim S, Lim P, Mao S, Sopha C, Sam B, Anderson JM, Meng Chuor C, Taylor WRJ, Suon S, Mercereau-Puijalon O, Fairhurst RM, Ménard D. 2013. Novel phenotypic assays for the detection of artemisininresistant Plasmodium falciparum malaria in Cambodia: in-vitro and exvivo drug-response studies. Lancet Infect. Dis. 13:1043-1049. http://dx .doi.org/10.1016/S1473-3099(13)70252-4.
53. Witkowski B, Khim N, Chim P, Kim S, Ke S, Kloeung N, Chy S, Duong S, Leang R, Ringwald P, Dondorp AM, Tripura R, Benoit-Vical F, Berry A, Gorgette O, Ariey F, Barale JC, Mercereau-Puijalon O, Ménard D. 2013. Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia. Antimicrob. Agents Chemother. 57:914-923. http://dx.doi.org/10.1128/AAC.01868-12.
54. Ariey F, Witkowsky B, Amaratunga C, Beghain J, Langlois AC, Khim N, Kim S, Duru V, Bouchier C, Ma L, Lim P, Leang R, Duong S, Sreng S, Suon S, Chuor CM, Bout DM, Ménard S, Rogers WO, Genton B, Fandeur T, Miotto O, Ringwald P, Le Bras J, Berry A, Barale JC, Fairhurst RM, Benoit-Vical F, Mercereau-Puijalon O, Ménard D. 2014. A molecular marker of artemisinin-resistant Plasmodium falciparum. Nature 505:50-55. http://dx.doi.org/10.1038/nature12876.
55. Poyomtip T, Suwandittakul N, Sitthichot N, Khositnithikul R, Tanariya, Mungthin PM. 2012. Polymorphisms of the pfmdr1 but not the pfnhe-1 gene is associated with in vitro quinine sensitivity in Thai isolates of Plasmodium falciparum. Malar. J. 11:7. http://dx.doi.org/10.1186/1475 -2875-11-7.
56. Baliraine FN, Nsobya SL, Achan J, Tibenderana JK, Talisuna AO, Greenhouse B, Rosenthal PJ. 2011. Limited ability of Plasmodium falciparum pfcrt, pfmdr1, and pfnhe1 polymorphisms to predict quinine in vitro sensitivity or clinical effectiveness in Uganda. Antimicrob. Agents Chemother. 55:615-622. http://dx.doi.org/10.1128/AAC.00954-10.
57. Folarin OA, Gbotosho GO, Sowunmi A, Olorunsogo OO, Oduola AMJ, Happi TC. 2008. Chloroquine resistant Plasmodium falciparum in Nigeria: relationship between pfcrt anf pfmdr1 polymorphisms, in vitro resistance and treatment outcome. Open Trop. Med. J. 1:74-82. http://dx.doi .org/10.2174/1874315300801010074.
58. Khim N, Bouchier C, Ekala MT, Incardona S, Lim P, Legrand E, Jambou R, Doung S, Puijalon OM, Fandeur T. 2005. Countrywide survey shows very high prevalence of Plasmodium falciparum multilocus resistance genotypes in Cambodia. Antimicrob. Agents Chemother. 49: 3147-3152. http://dx.doi.org/10.1128/AAC.49.8.3147-3152.2005.
59. Humphreys GS, Merinopoulos I, Ahmed J, Whitty CJ, Mutabingwa TK, Sutherland CJ, Hallett RL. 2007. Amodiaquine and artemetherlumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrob. Agents Chemother. 51:991-997. http://dx.doi.org/10.1128/AAC.00875-06.
60. Happi CT, Gbotosho GO, Folarin OA, Sowunmi A, Hudson T, O'Neil M, Milhous M, Wirth DF, Oduola AMJ. 2009. Selection of Plasmodium falciparum multidrug resistance gene 1 alleles in asexual stages and gametocytes by artemether-lumefantrine in Nigerian children with uncomplicated falciparum malaria. Antimicrob. Agents Chemother. 53:888-895. http://dx.doi.org/10.1128/AAC.00968-08.
61. Eyase FL, Akala HM, Ingasia L, Cheruiyot A, Omondi A, Okudo C, Juma D, Yeda R, Andagalu B, Wanja E, Kamau E, Schnabel D, Bulimo W, Waters NC, Walsh DS, Johnson JD. 2013. The role of Pfmdr1 and Pfcrt in changing chloroquine, amodiaquine, mefloquine and lumefantrine susceptibility in western-Kenya P. falciparum samples during 2008-2011. PLoS One 8:64299. http://dx.doi.org/10.1371/journal.pone.0064299.
62. Ochong EO, van den Broek IVF, Keus K, Nzila A. 2003. Association between chloroquine and amodiaquine resistance and allelic variation in the Plasmodium falciparum multiple drug resistance 1 gene and the chloroquine resistance transporter gene in isolates from the upper Nile in southern Sudan. Am. J. Trop. Med. Hyg. 69:184-187.
63. Happi CT, Gbotosho GO, Folarin OA, Bolaji OM, Sowunmi A, Kyle DE, Milhous W, Wirth DF, Oduola AMJ. 2006. Association between mutations in Plasmodium falciparum chloroquine resistance transporter and P. falciparum multidrug resistance 1 genes and in vivo amodiaquine resistance in P. falciparum malaria-infected children in Nigeria. Am. J. Trop. Med. Hyg. 75:155-161.
64. Mita T, Kanebo A, Hombhanje F, Hwaihwanje I, Takahashi N, Osawa H, Tsukahara T, Masta A, Lum JK, Kobayakawa T, Ishizaki T, Björkman A. 2006. Role of pfmdr1 mutations on chloroquine resistance in Plasmodium falciparum isolates with pfcrt K76T from Papua New Guinea. Acta Trop. 98:137-144. http://dx.doi.org/10.1016/j.actatropica.2006.03.002.
65. Sidhu AB, Uhlemann AC, Valderramos SG, Valderramos JC, Krishna S, Fidock D. 2006. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J. Infect. Dis. 194:528-535. http://dx .doi.org/10.1086/507115.
66. Lim P, Alker AP, Khim N, Shah NK, Incardona S, Doung S, Yi P, Bouth DM, Bouchier C, Puijalon OM, Meshnick SR, Wongsrichanalai C, Fandeur T, Le Bras J, Ringwald P, Ariey F. 2009. Pfmdr1 copy number and artemisinin derivative combination therapy failure in falciparum malaria in Cambodia. Malar. J. 8:11. http://dx.doi.org/10.1186/1475-2875-8-11.
67. Pascual A, Fall B, Wurtz N, Fall M, Camara C, Nakoulima A, Baret E, Diatta B, Wade B, Briolant S, Pradines B. 2013. Plasmodium falciparum with multidrug resistance 1 gene duplications, Senegal. Emerg. Infect. Dis. 19:814-815. http://dx.doi.org/10.3201/eid1905.121603.