SUKMAWATI BASUKI, 091170131 (2016) VARIASI GENETIK PLASMODIUM FALCIPARUM DIHYDROFOLATE REDUCTASE DAN DIHYDROPTEROATE SYNTHETASE SERTA IMPLIKASINYA TERHADAP PENGOBATAN SULFADOKSIN-PIRIMETAMIN DI KALIMANTAN SELATAN. Disertasi thesis, Universitas Airlangga.

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Abstract

Sulfadoxine-Pyrimethamine (SP) is still used in local area for malaria treatment in Indonesia. However, the genetic variations of pfdhfr, pfdhps and their correlations to SP treatment outcomes in Indonesia have not yet been well analyzed. In this dissertation, sequence polymorphisms of pfdhfr and pfdhps genes, and these correlations to SP treatment outcome were conducted in Banjar district, South Kalimantan. Three different alleles were determined in pfdhfr and six in pfdhps genes, both of which present simple accumulation patterns of mutation genotypes and support the stepwise mechanism of resistant gene evolution hypothesis. Two novel mutations of pfdhps, K540T and I588F, were determined in this area and these were correlated with low efficacy of SP treatment for uncomplicated falciparum malaria. Combined haplotypes pfdhfr/pfdhps containing either K540T or I588F in pfdhps showed that ANRNL/SGTGA tended to the early treatment failure and ANRNI/SGTGA and ANRNI/SGEAA (588F) tended to the late parasitological failure response parasites (containing equal or more than five mutations in pfdhfr/pfdhps haplotype, genotype marker of SP resistance). According to molecular modeling studies by de Beer T.A. et al and Lumb V. et al, K540 of PfDHPS is important for hydrogen bond formation with methoxy chain of sulfadoxine and mutations to neutral or acidic amino acids in this position decreased binding affinity to the drug. It suggested that two novel mutations of K540T and I588F in pfdhps can be used for a marker of P. falciparum resistant-SP and for monitoring SP resistance in several regions in Indonesia where SP resistant parasites have not been reported yet.

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