In Vivo Selection of Plasmodium Falciparum Parasites Carrying the Chloroquine-susceptible Pfcrt K76 Allele After Treatment with Artemether-lumefantrine in Africa

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2009 Feb 13

PMID 19210165

Citations 137

Authors

Christin Sisowath

Ines Petersen

M Isabel Veiga

Andreas Martensson

Zul Premji

Anders Bjorkman

David A Fidock

Jose P Gil

Affiliations

Soon will be listed here.

Abstract

Background: Artemether-lumefantrine (AL) is a major and highly effective artemisinin-based combination therapy that is becoming increasingly important as a new first-line therapy against Plasmodium falciparum malaria. However, recrudescences occurring after AL treatment have been reported. Identification of drug-specific parasite determinants that contribute to treatment failures will provide important tools for the detection and surveillance of AL resistance.

Methods: The findings from a 42-day follow-up efficacy trial in Tanzania that compared AL with sulfadoxine-pyrimethamine (SP) were analyzed to identify candidate markers for lumefantrine tolerance/resistance in the chloroquine resistance transporter gene (pfcrt) and multidrug resistance gene 1 (pfmdr1). The findings were corroborated in vitro with genetically modified isogenic P. falciparum parasite lines.

Results: Treatment with AL selected for the chloroquine-susceptible pfcrt K76 allele (P < .0001) and, to a lesser extent, the pfmdr1 N86 (P = .048) allele among recurrent infections. These genotypes were not selected during SP treatment. No pfmdr1 gene amplifications were observed. Isogenic pfcrt-modified parasite lines demonstrated a 2-fold increase in susceptibility to lumefantrine, which was directly attributable to the K76T mutation.

Conclusions: Our findings suggest that the pfcrt K76T mutation is a drug-specific contributor to enhanced P. falciparum susceptibility to lumefantrine in vivo and in vitro, and they highlight the benefit of using AL in areas affected by chloroquine-resistant P. falciparum malaria.

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References

Michaelis S . STE6, the yeast a-factor transporter. Semin Cell Biol. 1993; 4(1):17-27. DOI: 10.1006/scel.1993.1003. View

Cooper R, Ferdig M, Su X, Ursos L, Mu J, Nomura T . Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum. Mol Pharmacol. 2001; 61(1):35-42. DOI: 10.1124/mol.61.1.35. View

Johnson D, Fidock D, Mungthin M, Lakshmanan V, Sidhu A, Bray P . Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol Cell. 2004; 15(6):867-77. PMC: 2943419. DOI: 10.1016/j.molcel.2004.09.012. View

Fidock D, Nomura T, Talley A, Cooper R, Dzekunov S, Ferdig M . Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell. 2000; 6(4):861-71. PMC: 2944663. DOI: 10.1016/s1097-2765(05)00077-8. View

Volkman S, Cowman A, Wirth D . Functional complementation of the ste6 gene of Saccharomyces cerevisiae with the pfmdr1 gene of Plasmodium falciparum. Proc Natl Acad Sci U S A. 1995; 92(19):8921-5. PMC: 41079. DOI: 10.1073/pnas.92.19.8921. View

Price R, Uhlemann A, van Vugt M, Brockman A, Hutagalung R, Nair S . Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis. 2006; 42(11):1570-7. PMC: 4337983. DOI: 10.1086/503423. View

Sidhu A, Verdier-Pinard D, Fidock D . Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science. 2002; 298(5591):210-3. PMC: 2954758. DOI: 10.1126/science.1074045. View

Price R, Cassar C, Brockman A, Duraisingh M, van Vugt M, White N . The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrob Agents Chemother. 1999; 43(12):2943-9. PMC: 89592. DOI: 10.1128/AAC.43.12.2943. View

Djimde A, Doumbo O, Cortese J, Kayentao K, Doumbo S, Diourte Y . A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med. 2001; 344(4):257-63. DOI: 10.1056/NEJM200101253440403. View

10.

Price R, Uhlemann A, Brockman A, McGready R, Ashley E, Phaipun L . Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004; 364(9432):438-447. PMC: 4337987. DOI: 10.1016/S0140-6736(04)16767-6. View

11.

White N . Qinghaosu (artemisinin): the price of success. Science. 2008; 320(5874):330-4. DOI: 10.1126/science.1155165. View

12.

Martensson A, Stromberg J, Sisowath C, Msellem M, Gil J, Montgomery S . 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. 2005; 41(8):1079-86. DOI: 10.1086/444460. View

13.

Mita T, Kaneko A, Lum J, Zungu I, Tsukahara T, Eto H . Expansion of wild type allele rather than back mutation in pfcrt explains the recent recovery of chloroquine sensitivity of Plasmodium falciparum in Malawi. Mol Biochem Parasitol. 2004; 135(1):159-63. DOI: 10.1016/j.molbiopara.2004.01.011. View

14.

Dokomajilar C, Nsobya S, Greenhouse B, Rosenthal P, Dorsey G . Selection of Plasmodium falciparum pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrob Agents Chemother. 2006; 50(5):1893-5. PMC: 1472234. DOI: 10.1128/AAC.50.5.1893-1895.2006. View

15.

Valderramos S, Fidock D . Transporters involved in resistance to antimalarial drugs. Trends Pharmacol Sci. 2006; 27(11):594-601. PMC: 2944664. DOI: 10.1016/j.tips.2006.09.005. View

16.

Uhlemann A, Ramharter M, Lell B, Kremsner P, Krishna S . Amplification of Plasmodium falciparum multidrug resistance gene 1 in isolates from Gabon. J Infect Dis. 2005; 192(10):1830-5. DOI: 10.1086/497337. View

17.

Veiga M, Ferreira P, Bjorkman A, Gil J . Multiplex PCR-RFLP methods for pfcrt, pfmdr1 and pfdhfr mutations in Plasmodium falciparum. Mol Cell Probes. 2006; 20(2):100-4. DOI: 10.1016/j.mcp.2005.10.003. View

18.

Wongsrichanalai C, Meshnick S . Declining artesunate-mefloquine efficacy against falciparum malaria on the Cambodia-Thailand border. Emerg Infect Dis. 2008; 14(5):716-9. PMC: 2600243. DOI: 10.3201/eid1405.071601. View

19.

Duraisingh M, Jones P, Sambou I, von Seidlein L, Pinder M, Warhurst D . 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. 2000; 108(1):13-23. DOI: 10.1016/s0166-6851(00)00201-2. View

20.

Mita T, Kaneko A, Lum J, Bwijo B, Takechi M, Zungu I . Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi. Am J Trop Med Hyg. 2003; 68(4):413-5. View