Abstract
BackgroundTo use pyrimethamine as an alternative anti-malarial drug for chloroquine-resistant malaria parasites, it was necessary to determine the enzyme's genetic variation in dihydrofolate reductase-thymidylate syntase (DHFR-TS) among Korean strains.MethodsGenetic variation of dhfr-ts genes of Plasmodium vivax clinical isolates from patients who did not respond to drug treatment (n = 11) in Korea were analysed. The genes were amplified using the polymerase chain reaction (PCR) with genomic DNA as a template.ResultsSequence analysis showed that the open reading frame (ORF) of 1,857 nucleotides encoded a deduced protein of 618 amino acids (aa). Alignment with the DHFR-TS genes of other malaria parasites showed that a 231-residue DHFR domain and a 286-residue TS domain were seperated by a 101-aa linker region. This ORF shows 98.7% homology with the P. vivax Sal I strain (XM001615032) in the DHFR domain, 100% in the linker region and 99% in the TS domain. Comparison of the DHFR sequences from pyrimethamine-sensitive and pyrimethamine-resistant P. vivax isolates revealed that nine isolates belonged to the sensitive strain, whereas two isolates met the criteria for resistance. In these two isolates, the amino acid at position 117 is changed from serine to asparagine (S117N). Additionally, all Korean isolates showed a deletion mutant of THGGDN in short tandem repetitive sequences between 88 and 106 amino acid.ConclusionsThese results suggest that sequence variations in the DHFR-TS represent the prevalence of antifolate-resistant P. vivax in Korea. Two of 11 isolates have the Ser to Asn mutation in codon 117, which is the major determinant of pyrimethamine resistance in P. vivax. Therefore, the introduction of pyrimethamine for the treatment of chloroquine-resistant vivax malaria as alternative drug in Korea should be seriously considered.
Highlights
To use pyrimethamine as an alternative anti-malarial drug for chloroquine-resistant malaria parasites, it was necessary to determine the enzyme’s genetic variation in dihydrofolate reductase-thymidylate syntase (DHFR-thymidylate synthase (TS)) among Korean strains
Failed cases of chloroquine-primaquine combined treatment in Korea from 1996 to 2001 After a two-decades-long absence of vivax malaria in Korea, and starting with one patient who had served in the demilitarized zone (DMZ) as a soldier in 1993, the incidence of malaria increased rapidly [3,4,5,6,7]
Cloning of the dhfr -ts genes of P. vivax Korea isolates A total of 11 blood samples were collected from relapsed patients who visited the Public Health Care Centers located in Gyeonggido and Gangwondo in the malaria epidemic area of Korea
Summary
To use pyrimethamine as an alternative anti-malarial drug for chloroquine-resistant malaria parasites, it was necessary to determine the enzyme’s genetic variation in dihydrofolate reductase-thymidylate syntase (DHFR-TS) among Korean strains. As a result of a national malaria eradication program, and with help from the World Health Organization (WHO), the incidence of vivax malaria has rapidly decreased [2,3]. Vivax malaria was believed to have been eradicated in the Republic of Korea (ROK) since the late 1970 s, two sporadic cases were detected in the 1980 s [4]. These two patients relapsed after a long incubation. In 1993, a vivax malaria case was diagnosed among ROK army soldiers serving in the northern Gyeonggi-do [5]
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