Resistance to antifolates in Plasmodium falciparum, the causative agent of tropical malaria


Warhurst, DC; (2002) Resistance to antifolates in Plasmodium falciparum, the causative agent of tropical malaria. Science progress, 85 (Pt 1). pp. 89-111. ISSN 0036-8504

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Abstract

Every year there are 270 million clinical attacks of malaria and 2 million deaths, caused by the protozoan Plasmodium falciparum. Most of these cases occur in Africa. Chloroquine-resistance has led to reliance on anti-malarial antifolates, in particular the synergistic combination sulfadoxine/pyrimethamine (S/P) which targets enzymatic synthesis of folate co-factors through dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Resistance to S/P is now increasing and replacement antimalarials are needed. Crystal structures are not yet available for these key enzymes in the folate pathway. This review focuses on the activity of drugs on DHFR in malaria parasites, attempts to interpret differences in activity of pyrimethamine and its related drugs, and to clarify how residue changes due to point mutations determine the development of resistance. In homology-modelled P. falciparum DHFR (PfDHFR), the typical structure of four alpha-helices, 8-stranded beta-sheet, four Loops and eight Turns is clearly seen. Long polar sequences specific for Plasmodium are inserted in Turns 1 and 2. Structures immediately concerned in drug binding are beta-A, L1, alpha-B, alpha-C, T-3, beta-E, alpha-F, and beta-F. The roles of several mutations associated with resistance are discussed. In view of sequence differences in turn 3 in PfDHFR and in the human enzyme, and the marked interaction with residues of T3 of the experimental flexible antifolate WR99210 effective in pyrimethamine and cycloguanil resistance, further drug development in this area is indicated.

Item Type: Article
Keywords: Animal, Drug Resistance/*genetics, Folic Acid Antagonists/*pharmacology/therapeutic use, Human, Malaria, Falciparum/drug therapy/microbiology, Mutation/drug effects, Plasmodium falciparum/*drug effects/*genetics/metabolism, Animal, Drug Resistance, genetics, Folic Acid Antagonists, pharmacology, therapeutic use, Human, Malaria, Falciparum, drug therapy, microbiology, Mutation, drug effects, Plasmodium falciparum, drug effects, genetics, metabolism
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Research Centre: Antimicrobial Resistance Centre (AMR)
Malaria Centre
PubMed ID: 11969121
URI: http://researchonline.lshtm.ac.uk/id/eprint/16309

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