Chromosomal rearrangements and point mutations in the DHFR-TS gene of Plasmodium chabaudi under antifolate selection

https://doi.org/10.1016/0166-6851(90)90109-YGet rights and content

Abstract

Selection of the rodent malaria Plasmodium chabaudi with low levels of the antifolate drug pyrimethamine has previously been shown by us to result in duplication of the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene by a duplication of chromosome 7 and subsequent rearrangements. We have selected this resultant parasite line with large doses of pyrimethamine and analysed the DHFR-TS gene and chromosomes for any changes. Increased drug pressure has resulted in reappearance of a chromosome with the same structure as chromosome 7 from DS the parent line. Sequencing of the DHFR gene from each of the chromosomes has identified a single point mutation that results in a serine to asparagine change at position 106. This is the equivalent mutation that has been identified as the key residue in the mechanism of resistance to pyrimethamine in Plasmodium falciparum. There is no apparent increase in transcription of the DHFR-TS gene and the large increase in resistance is most likely a result of the mutation in the DHFR gene.

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    SDX resistance in P. falciparum has been linked with several point mutations on the pppk-dhps gene: S436A, A437G, K540E, A581G and A613S,T [40,41,42]. In the experimentally evolved P. chabaudi AS-PYR clone (Fig. 1) a DHFR S106N [21,43,44] mutation was selected (Fig. 3), which is homologous to S108N in P. falciparum. Interestingly, as also reported in P. falciparum [45], the acquisition of PYR resistance in P. chabaudi is accompanied by an increase in susceptibility to SDX [46].

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