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Pyrimethamine resistant mutations in Plasmodium falciparum.
S Thaithong1, S W Chan, S Songsomboon
1Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
Molecular and Biochemical Parasitology
|June 1, 1992
Summary
Mutations in the DHFR-TS enzyme and altered gene expression can increase pyrimethamine resistance in malaria parasites. These findings reveal two key mechanisms driving drug resistance in Plasmodium falciparum.
Area of Science:
- Malariology
- Molecular Parasitology
- Drug Resistance Mechanisms
Background:
- Pyrimethamine is a crucial antimalarial drug targeting dihydrofolate reductase-thymidylate synthase (DHFR-TS).
- Increasing resistance to pyrimethamine in Plasmodium falciparum threatens malaria control efforts.
Purpose of the Study:
- To investigate the molecular mechanisms underlying pyrimethamine resistance in Plasmodium falciparum.
- To identify genetic and non-genetic alterations conferring resistance.
Main Methods:
- Induction of mutations using chemical mutagens.
- Selection of resistant parasite clones in the presence of pyrimethamine.
- Analysis of DHFR-TS enzyme and gene sequence.
Main Results:
- A 500-fold increase in resistance was linked to a Ser108Asn mutation in DHFR-TS.
- A 10-fold resistance increase involved an Ile164Met mutation in DHFR-TS.
- A 100-fold resistance increase occurred without DHFR-TS gene mutation, but with doubled enzyme production.
Conclusions:
- Pyrimethamine resistance in P. falciparum can arise from structural DHFR-TS gene changes or alterations in gene expression.
- Understanding these mechanisms is vital for developing strategies against drug-resistant malaria.