Plasmodium falciparum:Mutation Pattern in the Dihydrofolate Reductase–Thymidylate Synthase Genes of Vietnamese Isolates, a Novel Mutation, and Coexistence of Two Clones in a Thai Patient

• Published in: Experimental parasitology Vol. 84; no. 1; pp. 56 - 64
• Main Authors: Zindrou, Sherwan, Dung, Nguyen Phuong, Sy, Nguyen Duy, Sköld, Ola, Swedberg, Göte
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.10.1996; Elsevier
• Subjects: Animals; antifolates; Antimalarials - pharmacology; Base Sequence; Biological and medical sciences; Classical genetics, quantitative genetics, hybrids; Cyc, cycloguanil; DNA, Protozoan - analysis; Drug Resistance - genetics; Fansidar; Folic Acid Antagonists - pharmacology; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Malaria, Falciparum - parasitology; Molecular Sequence Data; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium falciparum - genetics; Point Mutation; Proguanil; Protozoa; Pyr, pyrimethamine; Pyrimethamine - pharmacology; Sulfadoxine (a sulfonamide). DHFR, dihydrofolate reductase; Tetrahydrofolate Dehydrogenase - genetics; Thailand; Thymidylate Synthase - genetics; Triazines - pharmacology; TS, thymidylate synthase; Vietnam; VP, Vietnamese patients; Thailand; Asia; Vietnam; Plasmodium falciparum; Fansidar; Sulfadoxine (a sulfonamide). DHFR, dihydrofolate reductase; VP, Vietnamese patients; TS, thymidylate synthase; antifolates; Cyc, cycloguanil; Pyr, pyrimethamine; Protozoa; Antimalarial; Enzyme; Transferases; Thymidylate synthase; Resistance; Antiprotozoal agent; Methyltransferases; Gene; Parasiticid; Isolate; Oxidoreductases; Dihydrofolate reductase; Mutation; Sporozoa
• ISSN: 0014-4894; 1090-2449
• DOI: 10.1006/expr.1996.0089

ZINDROU, S., DUNG, N. P., SY, N. D., SKÖLD, O., and SWEDBERG, G. 1996.Plasmodium falciparum:Mutation pattern in the dihydrofolate reductase–thymidylate synthase genes of Vietnamese isolates, a novel mutation, and coexistence of two clones in a Thai patient.Experimental Parasitology84,56–64. Pyrimethamine and cycloguanil resistance ofPlasmodium falciparumhas been linked to mutations in the dihydrofolate reductase (dhfr) portion of thedhfr-tsgene. In this paper, the DNA sequence of thedhfr-tsgene of 50 isolates from Vietnam and 2 clones (T9/94 and T9/96) isolated from a malaria patient from Thailand have been analyzed. A comparison between these isolates and clones showed differential mutation patterns. Forty-eight isolates were found to consist of mutations associated with Pyrr. A novel leucine mutation at position 140 was found in the isolate VP8 and in clone T9/94. The isolate VP8 and the clone T9/94 were found to also have the characteristic changes at positions 16 (Val) and 108 (Thr) that have been found in cycloguanil-resistant isolates. The isolate VP35 was shown to be resistant to both antifolates, while the clone T9/96 was found to be sensitive to both antifolates and to have a sequence identical to that of wild-typedhfr-ts.The two clones from a single patient showed the coexistence of resistant and sensitive clones in the absence of treatment by antifolates. Since cycloguanil resistance seems to be rare in Vietnam, cycloguanil alone or in combination with other antimalarial agents might be an alternative for treatment and prophylaxis, even in areas with high resistance to pyrimethamine.