This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ASM journals
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nzila-Mounda, A.
Right arrow Articles by Watkins, W. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nzila-Mounda, A.
Right arrow Articles by Watkins, W. M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, January 1998, p. 164-169, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

A. Nzila-Mounda,1,2,3,* E. K. Mberu,1,4 C. H. Sibley,3 C. V. Plowe,5 P. A. Winstanley,6 and W. M. Watkins1,2,6

Wellcome Trust Research Laboratories,1 Kenya Medical Research Institute,2 and Department of Pharmaceutics and Pharmacy Practice, Faculty of Pharmacy, University of Nairobi,4 Nairobi, Kenya; University of Washington Department of Genetics, Seattle, Washington 98195-73603; University of Maryland, Division of Geographic Medicine and Entomology, Baltimore, Maryland 212015; and University of Liverpool, Department of Pharmacology and Therapeutics, Liverpool L69 3BX, United Kingdom6

Received 11 June 1997/Returned for modification 20 August 1997/Accepted 20 October 1997

Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P < 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

* Corresponding author. Mailing address: Wellcome Trust Research Laboratories, P.O. Box 43640, Nairobi, Kenya. Phone: 254 2 725 390 or 254 2 725 398. Fax: 254 2 711 673. E-mail: wellcome{at}users.africaonline.co.ke.

Antimicrobial Agents and Chemotherapy, January 1998, p. 164-169, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Carnevale, E. P., Kouri, D., DaRe, J. T., McNamara, D. T., Mueller, I., Zimmerman, P. A. (2007). A Multiplex Ligase Detection Reaction-Fluorescent Microsphere Assay for Simultaneous Detection of Single Nucleotide Polymorphisms Associated with Plasmodium falciparum Drug Resistance. J. Clin. Microbiol. 45: 752-761 [Abstract] [Full Text]  
  • MENARD, D., YAPOU, F., MANIRAKIZA, A., DJALLE, D., MATSIKA-CLAQUIN, M. D., TALARMIN, A. (2006). Polymorphisms in pfcrt, pfmdr1, dhfr genes and in vitro responses to antimalarials in Plasmodium falciparum isolates from bangui, central african republic.. Am J Trop Med Hyg 75: 381-387 [Abstract] [Full Text]  
  • Nzila, A. (2006). The past, present and future of antifolates in the treatment of Plasmodium falciparum infection. J Antimicrob Chemother 57: 1043-1054 [Abstract] [Full Text]  
  • BURNS, M., BAKER, J., AULIFF, A. M., GATTON, M. L., EDSTEIN, M. D., CHENG, Q. (2006). EFFICACY OF SULFADOXINE-PYRIMETHAMINE IN THE TREATMENT OF UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA IN EAST TIMOR.. Am J Trop Med Hyg 74: 361-366 [Abstract] [Full Text]  
  • HAPUARACHCHI, H. C., DAYANATH, M. Y. D., BANDARA, K. B. A. T., ABEYSUNDARA, S., ABEYEWICKREME, W., DE SILVA, N. R., HUNT, S. Y., SIBLEY, C. H. (2006). POINT MUTATIONS IN THE DIHYDROFOLATE REDUCTASE AND DIHYDROPTEROATE SYNTHASE GENES OF PLASMODIUM FALCIPARUM AND RESISTANCE TO SULFADOXINE-PYRIMETHAMINE IN SRI LANKA. Am J Trop Med Hyg 74: 198-204 [Abstract] [Full Text]  
  • SAMUDIO, F., SANTAMARIA, A. M., OBALDIA, N. I., PASCALE, J. M., BAYARD, V., CALZADA, J. E. (2005). PREVALENCE OF PLASMODIUM FALCIPARUM MUTATIONS ASSOCIATED WITH ANTIMALARIAL DRUG RESISTANCE DURING AN EPIDEMIC IN KUNA YALA, PANAMA, CENTRAL AMERICA. Am J Trop Med Hyg 73: 839-841 [Abstract] [Full Text]  
  • Gregson, A., Plowe, C. V. (2005). Mechanisms of Resistance of Malaria Parasites to Antifolates. Pharmacol. Rev. 57: 117-145 [Abstract] [Full Text]  
  • Mbaisi, A., Liyala, P., Eyase, F., Achilla, R., Akala, H., Wangui, J., Mwangi, J., Osuna, F., Alam, U., Smoak, B. L., Davis, J. M., Kyle, D. E., Coldren, R. L., Mason, C., Waters, N. C. (2004). Drug Susceptibility and Genetic Evaluation of Plasmodium falciparum Isolates Obtained in Four Distinct Geographical Regions of Kenya. Antimicrob. Agents Chemother. 48: 3598-3601 [Abstract] [Full Text]  
  • ZIMMERMAN, P. A. (2003). ROLL BACK OF PLASMODIUM FALCIPARUM ANTIFOLATE RESISTANCE BY INSECTICIDE-TREATED NETS. Am J Trop Med Hyg 69: 236-237 [Full Text]  
  • BASCO, L. K. (2003). MOLECULAR EPIDEMIOLOGY OF MALARIA IN CAMEROON. XV. EXPERIMENTAL STUDIES ON SERUM SUBSTITUTES AND SUPPLEMENTS AND ALTERNATIVE CULTURE MEDIA FOR IN VITRO DRUG SENSITIVITY ASSAYS USING FRESH ISOLATES OF PLASMODIUM FALCIPARUM. Am J Trop Med Hyg 69: 168-173 [Abstract] [Full Text]  
  • Hastings, M. D., Sibley, C. H. (2002). Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax. Proc. Natl. Acad. Sci. USA 99: 13137-13141 [Abstract] [Full Text]  
  • Lau, H., Ferlan, J. T., Brophy, V. H., Rosowsky, A., Sibley, C. H. (2001). Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa. Antimicrob. Agents Chemother. 45: 187-195 [Abstract] [Full Text]  
  • Nzila, A. M., Mberu, E. K., Sulo, J., Dayo, H., Winstanley, P. A., Sibley, C. H., Watkins, W. M. (2000). Towards an Understanding of the Mechanism of Pyrimethamine-Sulfadoxine Resistance in Plasmodium falciparum: Genotyping of Dihydrofolate Reductase and Dihydropteroate Synthase of Kenyan Parasites. Antimicrob. Agents Chemother. 44: 991-996 [Abstract] [Full Text]  
  • Shallom, S., Zhang, K., Jiang, L., Rathod, P. K. (1999). Essential Protein-Protein Interactions between Plasmodium falciparum Thymidylate Synthase and Dihydrofolate Reductase Domains. J. Biol. Chem. 274: 37781-37786 [Abstract] [Full Text]  
  • Basco, L. K., Tahar, R., Ringwald, P. (1998). Molecular Basis of In Vivo Resistance to Sulfadoxine-Pyrimethamine in African Adult Patients Infected with Plasmodium falciparum Malaria Parasites. Antimicrob. Agents Chemother. 42: 1811-1814 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»