Abstract
BackgroundSulphadoxine and pyrimethamine are anti-folate drugs that show synergistic anti-malarial effect. Point mutations in dihydrofolate reductase (dhfr) and dihydropteorate synthatase (dhps) cause anti-folate drug resistance phenotype in human malaria parasites. This study presents pattern of point mutations in dhfr/dhps genes among Indian sub-continent.MethodsMicroscopically diagnosed one hundred Plasmodium vivax field isolates were collected from five widely separated geographical regions of India. Dhfr and dhps genes were PCR amplified and sequenced. Previously published mutations data were collected and analyzed using Chi square test to identify geographical cluster of mutant/wild type genotypes.ResultsSequence analysis revealed single (S58R), double (S58R/S117N) and quadruple (F57L/S58R/T61M/S117T/) point mutations at dhfr and single (A383G) to double (A383G/A553G) mutations at dhps in P. vivax field isolates. In addition, three new mutations were also observed at dhfr. Both, dhfr and dhps genes revealed tandem repeat variations in field isolates. Dhps revealed very low mutation frequency (14.0%) compared to dhfr (50.70%). Comparative analysis revealed a progressive increase in frequency of quadruple mutant dhfr genotype (p < 0.001) within five years in north-eastern state (Kamrup, Assam). Frequency of dhfr genotypes revealed three distinct geographical clusters of wild (northern India), double mutant (southern India), and quadruple mutant (north-eastern and island regions of India) on the Indian sub-continent.ConclusionStudy suggests that SP may be susceptible to P. vivax in India, except Andaman and north-eastern state. The distinction of geographical regions with sensitive and resistant parasite phenotypes would be highly useful for designing and administering national anti-malarial drug policy.
Highlights
Sulphadoxine and pyrimethamine are anti-folate drugs that show synergistic anti-malarial effect
This study aims to identify point mutations in dhfr/dhps and the spatio temporal pattern of anti-folate drug resistance in Indian sub-continent
Point mutations observed at dhfr were given in table 1
Summary
Sulphadoxine and pyrimethamine are anti-folate drugs that show synergistic anti-malarial effect. Point mutations in dihydrofolate reductase (dhfr) and dihydropteorate synthatase (dhps) cause anti-folate drug resistance phenotype in human malaria parasites. The worldwide spread of chloroquine (CQ) resistant strains of P. falciparum has led to use of sulphadoxinepyrimethamine (SP) as the first-line anti-malarial drug in Southeast Asian countries. To overcome CQ resistance problem, in 1982, SP was employed as first-line anti-malarial therapy for treatment of falciparum malaria in areas with >25% CQ resistant level, complicated malaria case, and higher malaria endemicity [12]. According to the national anti-malarial drug policy, artimisinin-based combination therapy (ACT) (Artesunate+SP) is being used in most of the malaria endemic regions [12]
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