PLASMODIUM-FALCIPARUM - MUTATION PATTERN IN THE DIHYDROFOLATE-REDUCTASE THYMIDYLATE SYNTHASE GENES OF VIETNAMESE ISOLATES, A NOVEL MUTATION, AND COEXISTENCE OF 2 CLONES IN A THAI PATIENT

Pyrimethamine and cycloguanil resistance of Plasmodium falciparum has been linked to mutations in the dihydrofolate reductase (dhfr) portion of the dhfr-ts gene. In this paper, the DNA sequence of the dhfr-ts g ene of 50 isolates from Vietnam and 2 clones (T9/94 and T9/96) isolate d from a malaria patient from Thailand have been analyzed. A compariso n between these isolates and clones showed differential mutation patte rns. Forty-eight isolates were found to consist of mutations associate d with Pyr(r). A novel leucine mutation at position 140 was found in t he 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 (V al) and 108 (Thr) that have been found in cycloguanil-resistant isolat es. The isolate VP35 was shown to be resistant to both antifolates, wh ile the clone T9/96 was found to be sensitive to both antifolates and to have a sequence identical to that of wild-type dhfr-ts. The two clo nes from a single patient showed the coexistence of resistant and sens itive clones in the absence of treatment by antifolates. Since cyclogu anil resistance seems to be rare in Vietnam, cycloguanil alone or in c ombination with other antimalarial agents might be an alternative for treatment and prophylaxis, even in areas with high resistance to pyrim ethamine. (C) 1996 Academic Press. Inc.