Skip to main content
Top
Published in: Malaria Journal 1/2007

Open Access 01-12-2007 | Research

Analysis of sulphadoxine/pyrimethamine resistance-conferring mutations of Plasmodium falciparum from Mozambique reveals the absence of the dihydrofolate reductase 164L mutant

Authors: Natércia Fernandes, Paula Figueiredo, Virgilio E do Rosário, Pedro Cravo

Published in: Malaria Journal | Issue 1/2007

Login to get access

Abstract

Background

Plasmodium falciparum is the predominant human malaria species in Mozambique and a lead cause of mortality among children and pregnant women nationwide. Sulphadoxine/pyrimethamine (S/P) is used as first line antimalarial treatment as a partner drug in combination with artesunate.

Methods

A total of 92 P. falciparum-infected blood samples, from children with uncomplicated malaria attending the Centro de Saude de Bagamoyo in the Province of Maputo-Mozambique, were screened for S/P resistance-conferring mutations in the pfdhfr and pfdhps genes using a nested mutation-specific polymerase chain reaction and restriction digestion (PCR-RFLP). The panel of genetic polymorphisms analysed included the pfdhfr 164L mutation, previously reported to be absent or rare in Africa.

Results

The frequency of the S/P resistance-associated pfdhfr triple mutants (51I/59R/108N) and of pfdhfr/pfdhps quintuple mutants (51I/59R/108N + 437G/540E) was 93% and 47%, respectively. However, no pfdhfr 164L mutants were detected.

Conclusion

The observation that a considerably high percentage of P. falciparum parasites contained S/P resistance-associated mutations raises concerns about the validity of this drug as first-choice treatment in Mozambique. On the other hand, no pfdhfr 164L mutant was disclosed, corroborating the view that that this allele is still rare in Africa.
Appendix
Available only for authorised users
Literature
1.
go back to reference World Health Organization: Guidelines for the treatment of malaria. Document WHO/HTM/MAL/2006.1108, Geneva: WHO. 2006 World Health Organization: Guidelines for the treatment of malaria. Document WHO/HTM/MAL/2006.1108, Geneva: WHO. 2006
2.
go back to reference Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR: Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002, 2: 209-218. 10.1016/S1473-3099(02)00239-6.CrossRefPubMed Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR: Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002, 2: 209-218. 10.1016/S1473-3099(02)00239-6.CrossRefPubMed
3.
go back to reference Le Bras J, Durand R: The mechanisms of resistance toantimalarial drugs in Plasmodium falciparum. Fundam Clin Pharmacol. 2003, 17: 147-53. 10.1046/j.1472-8206.2003.00164.x.CrossRefPubMed Le Bras J, Durand R: The mechanisms of resistance toantimalarial drugs in Plasmodium falciparum. Fundam Clin Pharmacol. 2003, 17: 147-53. 10.1046/j.1472-8206.2003.00164.x.CrossRefPubMed
4.
go back to reference Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe CV: Molecular markers forfailure of sulphadoxine-pyrimethamine and chlorproguanil-dapsonetreatment of Plasmodium falciparum malaria. J Infect Dis. 2002, 185: 380-388. 10.1086/338566.CrossRefPubMed Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe CV: Molecular markers forfailure of sulphadoxine-pyrimethamine and chlorproguanil-dapsonetreatment of Plasmodium falciparum malaria. J Infect Dis. 2002, 185: 380-388. 10.1086/338566.CrossRefPubMed
5.
go back to reference Mockenhaupt FP, Bousema TJ, Eggelte TA, Schreiber J, Ehrhardt S, Wassilew N, Otchwemah RN, Sauerwein RW, Bienzle U: Plasmodium falciparum dhfr but not dhps mutations associated with sulphadoxine-pyrimethamine treatmentfailure and gametocyte carriage in northern Ghana. Trop Med Int Health. 2005, 10: 901-908. 10.1111/j.1365-3156.2005.01471.x.CrossRefPubMed Mockenhaupt FP, Bousema TJ, Eggelte TA, Schreiber J, Ehrhardt S, Wassilew N, Otchwemah RN, Sauerwein RW, Bienzle U: Plasmodium falciparum dhfr but not dhps mutations associated with sulphadoxine-pyrimethamine treatmentfailure and gametocyte carriage in northern Ghana. Trop Med Int Health. 2005, 10: 901-908. 10.1111/j.1365-3156.2005.01471.x.CrossRefPubMed
6.
go back to reference Urdaneta L, Plowe C, Goldman I, Lal AA: Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela. Am J Trop Med Hyg. 1999, 61: 457-462.PubMed Urdaneta L, Plowe C, Goldman I, Lal AA: Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela. Am J Trop Med Hyg. 1999, 61: 457-462.PubMed
7.
go back to reference Watkins WM, Mberu EK, Winstanley PA, Plowe CV: The Efficacy of antifolate antimalarial combination in africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses. Parasitol Today. 1997, 13: 459-464. 10.1016/S0169-4758(97)01124-1.CrossRefPubMed Watkins WM, Mberu EK, Winstanley PA, Plowe CV: The Efficacy of antifolate antimalarial combination in africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses. Parasitol Today. 1997, 13: 459-464. 10.1016/S0169-4758(97)01124-1.CrossRefPubMed
8.
go back to reference Basco LK, Eldin de Pecoulas P, Wilson CM, Le Bras J, Mazabraud A: Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum. Mol Biochem Parasitol. 1995, 69: 135-138. 10.1016/0166-6851(94)00207-4.CrossRefPubMed Basco LK, Eldin de Pecoulas P, Wilson CM, Le Bras J, Mazabraud A: Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum. Mol Biochem Parasitol. 1995, 69: 135-138. 10.1016/0166-6851(94)00207-4.CrossRefPubMed
9.
go back to reference Basco LK, de Pecoulas PE, Le Bras J, Wilson CM: Plasmodium falciparum: molecular characterization of multidrug-resistant Cambodian isolates. Exp Parasitol. 1996, 82: 97-103. 10.1006/expr.1996.0013.CrossRefPubMed Basco LK, de Pecoulas PE, Le Bras J, Wilson CM: Plasmodium falciparum: molecular characterization of multidrug-resistant Cambodian isolates. Exp Parasitol. 1996, 82: 97-103. 10.1006/expr.1996.0013.CrossRefPubMed
10.
go back to reference Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, Winstanley PA, Estrada-Franco JG, Mollinedo RE, Avila JC, Cespedes JL, Carter D, Doumbo OK: Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulphadoxine use and resistance. J Infect Dis. 1997, 176: 1590-1596.CrossRefPubMed Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, Winstanley PA, Estrada-Franco JG, Mollinedo RE, Avila JC, Cespedes JL, Carter D, Doumbo OK: Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulphadoxine use and resistance. J Infect Dis. 1997, 176: 1590-1596.CrossRefPubMed
11.
go back to reference Zindrou S, Nguyen PD, Nguyen DS, Skold O, Swedberg G: Plasmodium falciparum: mutation pattern in the dihydrofolate reductase-thymidylate synthase genes of Vietnamese isolates, a novel mutation, and coexistence of two clones in a Thai patient. Exp Parasitol. 1996, 84: 56-64. 10.1006/expr.1996.0089.CrossRefPubMed Zindrou S, Nguyen PD, Nguyen DS, Skold O, Swedberg G: Plasmodium falciparum: mutation pattern in the dihydrofolate reductase-thymidylate synthase genes of Vietnamese isolates, a novel mutation, and coexistence of two clones in a Thai patient. Exp Parasitol. 1996, 84: 56-64. 10.1006/expr.1996.0089.CrossRefPubMed
12.
go back to reference Nzila A, Ochong E, Nduati E, Gilbert K, Winstanley P, Ward S, Marsh K: Why has the dihydrofolate reductase 164 mutation not consistently been found in Africa yet ?. Trans R Soc Trop Med Hyg. 2005, 99: 341-346. 10.1016/j.trstmh.2004.07.002.CrossRefPubMed Nzila A, Ochong E, Nduati E, Gilbert K, Winstanley P, Ward S, Marsh K: Why has the dihydrofolate reductase 164 mutation not consistently been found in Africa yet ?. Trans R Soc Trop Med Hyg. 2005, 99: 341-346. 10.1016/j.trstmh.2004.07.002.CrossRefPubMed
13.
go back to reference Duraisingh MT, Curtis J, Warhurst DC: Plasmodium falciparum: Detection of polymorphisms in the dihydrofolate reductase and dihydropteroato synthase genes by PCR and restriction digestion. Exp Parasitol. 1998, 89: 1-8. 10.1006/expr.1998.4274.CrossRefPubMed Duraisingh MT, Curtis J, Warhurst DC: Plasmodium falciparum: Detection of polymorphisms in the dihydrofolate reductase and dihydropteroato synthase genes by PCR and restriction digestion. Exp Parasitol. 1998, 89: 1-8. 10.1006/expr.1998.4274.CrossRefPubMed
14.
go back to reference Alifrangis M, Enosse S, Khalil IF, Tarimo DS, Lemnge MM, Thompson R, Bygbjerg IC, Ronn AM: Prediction of Plasmodium falciparum resistance to sulphadoxine/pyrimethamine in vivo by mutations in the dihydrofolate reductase and dihydropteroate synthetase genes: a comparative study between sites of differing endemicity. Am J Trop Med Hyg. 2003, 69: 601-606.PubMed Alifrangis M, Enosse S, Khalil IF, Tarimo DS, Lemnge MM, Thompson R, Bygbjerg IC, Ronn AM: Prediction of Plasmodium falciparum resistance to sulphadoxine/pyrimethamine in vivo by mutations in the dihydrofolate reductase and dihydropteroate synthetase genes: a comparative study between sites of differing endemicity. Am J Trop Med Hyg. 2003, 69: 601-606.PubMed
15.
go back to reference Abacassamo F, Enosse S, Aponte JJ, Gomez-Olive FX, Quinto L, Mabunda S, Barreto A, Magnussen P, Ronn AM, Thompson R, Alonso PL, Abacassamo F, Enosse S, Aponte JJ, Gomez-Olive FX, Quinto L, Mabunda S, Barreto A, Magnussen P, Ronn AM, Thompson R, Alonso PL: Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria. Trop Med Int Health. 2004, 9: 200-208. 10.1046/j.1365-3156.2003.01182.x.CrossRefPubMed Abacassamo F, Enosse S, Aponte JJ, Gomez-Olive FX, Quinto L, Mabunda S, Barreto A, Magnussen P, Ronn AM, Thompson R, Alonso PL, Abacassamo F, Enosse S, Aponte JJ, Gomez-Olive FX, Quinto L, Mabunda S, Barreto A, Magnussen P, Ronn AM, Thompson R, Alonso PL: Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria. Trop Med Int Health. 2004, 9: 200-208. 10.1046/j.1365-3156.2003.01182.x.CrossRefPubMed
16.
go back to reference Alker AP, Mwapasa V, Purfield A, Rogerson SJ, Molyneux ME, Kamwendo DD, Tadesse E, Chaluluka E, Meshnick SR: Mutations associated with sulphadoxine-pyrimethamine and chlorproguanil resistance in Plasmodium falciparum isolates from Blantyre, Malawi. Antimicrob Agents Chemother. 2005, 49: 3919-3921. 10.1128/AAC.49.9.3919-3921.2005.PubMedCentralCrossRefPubMed Alker AP, Mwapasa V, Purfield A, Rogerson SJ, Molyneux ME, Kamwendo DD, Tadesse E, Chaluluka E, Meshnick SR: Mutations associated with sulphadoxine-pyrimethamine and chlorproguanil resistance in Plasmodium falciparum isolates from Blantyre, Malawi. Antimicrob Agents Chemother. 2005, 49: 3919-3921. 10.1128/AAC.49.9.3919-3921.2005.PubMedCentralCrossRefPubMed
17.
go back to reference Mutabingwa T, Nzila A, Mberu E, Nduati E, Winstanley P, Hills E, Watkins W: Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania. Lancet. 2001, 358: 1218-1223. 10.1016/S0140-6736(01)06344-9.CrossRefPubMed Mutabingwa T, Nzila A, Mberu E, Nduati E, Winstanley P, Hills E, Watkins W: Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania. Lancet. 2001, 358: 1218-1223. 10.1016/S0140-6736(01)06344-9.CrossRefPubMed
18.
go back to reference Curtis J, Maxwell CA, Msuya FH, Mkongewa S, Alloueche A, Warhurst DC: Mutations in dhfr in Plasmodium falciparum infections selected by chlorproguanil-dapsone treatment. J Infect Dis. 2002, 186: 1861-1864. 10.1086/345765.CrossRefPubMed Curtis J, Maxwell CA, Msuya FH, Mkongewa S, Alloueche A, Warhurst DC: Mutations in dhfr in Plasmodium falciparum infections selected by chlorproguanil-dapsone treatment. J Infect Dis. 2002, 186: 1861-1864. 10.1086/345765.CrossRefPubMed
19.
go back to reference Hastings MD, Bates SJ, Blackstone EA, Monks SM, Mutabingwa TK, Sibley CH: Highly pyrimethamine-resistant alleles of dihydrofolate reductase in isolates of Plasmodium falciparum from Tanzania. Trans R Soc Trop Med Hyg. 2002, 96: 674-676. 10.1016/S0035-9203(02)90349-4.CrossRefPubMed Hastings MD, Bates SJ, Blackstone EA, Monks SM, Mutabingwa TK, Sibley CH: Highly pyrimethamine-resistant alleles of dihydrofolate reductase in isolates of Plasmodium falciparum from Tanzania. Trans R Soc Trop Med Hyg. 2002, 96: 674-676. 10.1016/S0035-9203(02)90349-4.CrossRefPubMed
Metadata
Title
Analysis of sulphadoxine/pyrimethamine resistance-conferring mutations of Plasmodium falciparum from Mozambique reveals the absence of the dihydrofolate reductase 164L mutant
Authors
Natércia Fernandes
Paula Figueiredo
Virgilio E do Rosário
Pedro Cravo
Publication date
01-12-2007
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2007
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/1475-2875-6-35

Other articles of this Issue 1/2007

Malaria Journal 1/2007 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine