Open AccessIn vitro susceptibilities of Plasmodium falciparum to compounds which inhibit nucleotide metabolism
Author(s) -
Susan A. Queen,
David L. Vander Jagt,
Philip Reyes
Publication year - 1990
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.34.7.1393
Subject(s) - plasmodium falciparum , purine , hypoxanthine , biology , biochemistry , nucleotide , nucleotide salvage , purine metabolism , de novo synthesis , guanine , antimalarial agent , purine analogue , in vitro , pyrimidine , pyrimidine metabolism , enzyme , malaria , immunology , gene
A unique metabolic feature of malaria parasites is their restricted ability to synthesize nucleotides. These parasites are unable to synthesize the purine ring and must therefore obtain preformed purine bases and nucleosides from the host cell, the erythrocyte. On the other hand, pyrimidines must be synthesized de novo because of the inability of the parasites to salvage preformed pyrimidines. Thus, one would anticipate that the blockage of purine salvage or pyrimidine de novo synthesis should adversely affect parasite growth. This premise was tested in vitro with a total of 64 compounds, mostly purine and pyrimidine analogs, known to inhibit one or more steps of nucleotide synthesis. Of the 64 compounds, 22 produced a 50% inhibition of the growth of the human malaria parasite Plasmodium falciparum at a concentration of 50 microM or less. Inhibition of the growth of chloroquine-resistant clones of P. falciparum did not differ significantly from that of the growth of chloroquine-susceptible clones. Two of the compounds which effectively inhibited parasite growth, 6-mercaptopurine and 6-thioguanine, were found to be potent competitive inhibitors of a key purine-salvaging enzyme (hypoxanthine-guanine-xanthine phosphoribosyltransferase) of the parasite.