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Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization.
- Source :
-
Molecular microbiology [Mol Microbiol] 1997 Mar; Vol. 23 (5), pp. 979-86. - Publication Year :
- 1997
-
Abstract
- Sulfadoxine/pyrimethamine (Fansidar) is widely used in Africa for treating chloroquine-resistant falciparum malaria. To clarify how parasite resistance to this combination arises, various lines of Plasmodium falciparum were used to investigate the role of naturally occurring mutations in the target enzyme, dihydropteroate synthetase (DHPS), in the parasite response to sulfadoxine inhibition. An improved drug assay was employed to identify a clear correlation between sulfadoxine-resistance levels and the number of DHPS mutations. Moreover, tight linkage was observed between DHPS mutations and high-level resistance in the 16 progeny of a genetic cross between sulfadoxine-sensitive (HB3) and sulfadoxine-resistant (Dd2) parents. However, we also demonstrate a profound influence of exogenous folate on IC50 values, which, under physiological conditions, may have a major role in determining resistance levels. Importantly, this phenotype does not segregate with dhps genotypes in the cross, but shows complete linkage to the two alleles of the dihydrofolate reductase (dhfr) gene inherited from the parental lines. However, in unrelated lines, this folate effect correlates less well with DHFR sequence, indicating that the gene responsible may be closely linked to dhfr, rather than dhfr itself. These results have major implications for the acquisition of Fansidar resistance by malaria parasites.
- Subjects :
- Alleles
Animals
Antimalarials metabolism
Antimalarials therapeutic use
Drug Antagonism
Drug Combinations
Drug Resistance, Microbial genetics
Folic Acid metabolism
Folic Acid pharmacology
Genetic Linkage
Humans
Malaria, Falciparum drug therapy
Microbial Sensitivity Tests
Plasmodium falciparum metabolism
Polymerase Chain Reaction
Pyrimethamine metabolism
Pyrimethamine therapeutic use
Recombination, Genetic
Sequence Analysis, DNA
Sulfadoxine metabolism
Sulfadoxine therapeutic use
Antimalarials pharmacology
Dihydropteroate Synthase genetics
Plasmodium falciparum drug effects
Plasmodium falciparum genetics
Pyrimethamine pharmacology
Sulfadoxine pharmacology
Tetrahydrofolate Dehydrogenase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0950-382X
- Volume :
- 23
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular microbiology
- Publication Type :
- Academic Journal
- Accession number :
- 9076734
- Full Text :
- https://doi.org/10.1046/j.1365-2958.1997.2821646.x