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Journal of Postgraduate Medicine
Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India
ISSN: 0022-3859
EISSN: 0022-3859
Vol. 50, No. 1, 2004, pp. 17-20
Bioline Code: jp04006
Full paper language: English
Document type: Research Article
Document available free of charge

Journal of Postgraduate Medicine, Vol. 50, No. 1, 2004, pp. 17-20

 en Associations of antifolate resistance in vitro and point mutations in dihydrofolate reductase and dihydropteroate synthetase genes of Plasmodium falciparum check for this species in other resources
Biswas S

Abstract

Background: Antifolate antimalarials like sulfadoxine-pyrimethamine are used as second-line treatment for Plasmodium falciparum check for this species in other resources malaria patients who fail to respond to chloroquine. The efficacy of the sulfa-pyrimethamine combination in the treatment is also compromised by the development of resistance in the parasite. Resistance to these drugs has been shown to encode with point mutations in dihydrofolate reductase and dihydropteroate synthetase genes.
Settings: An experimental study.
Maerial and methods: Forty clinical isolates collected from different geographical locations in India were used to assess the relationships between resistance to sulfadoxine-pyrimethamine (SP) and mutations in P. falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS). In vitro drug susceptibility and mutation-specific polymerase chain reaction (PCR) assays were also done.
Results: It was observed that a number of isolates possessed mutant genotypes and showed low sensitivity to SP in vitro. Of the 40 clinical isolates studied, 87.5% had DHFR and 15% had DHPS gene mutations. As observed from PCR results, 55( (22/40) presented double mutation of DHFR Arg-59 and Asn-108 and 32.5 % (13/40) had single mutant type allele of Asn-108. Of the 40 isolates, 10 % (4/40) presented doubly mutated forms of DHPS Phe-436 and Thr-613 and single mutant type allele Gly-581 was detected in 5 % (2/40) isolates. Parasites carrying double or single mutant forms of DHFR/DHPS showed elevated minimum inhibitory concentration (MIC) values of both pyrimethamine (760-6754 nM; r=0.69) and sulfadoxine (108 - 540 μM; r=0.87) when compared to sensitive and resistant strains.
Conclusion: Though there was a correlation between molecular techniques and in vitro drug sensitivity profiles, the relevance of these findings to the clinical efficacy of SP combination drugs needs to be established by controlled clinical trials.

Keywords
Malaria, P. falciparum, in vitro culture, drug sensitivity, point mutation, DHFR, DHPS

 
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