title: Effects of dual combinations of antifolates with atovaquone or dapsone on nucleotide levels in Plasmodium falciparum.
abstract: The triazine antifolates, cycloguanil and 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[(2,4,5-trichlorophenoxy)propy loxy]-1,3,5-triazine hydrobromide (WR99210), and their parent biguanide compounds, proguanil and N-[3-(2,4,5-trichlorophenoxy)propyloxy]-n-(1-methylethyl)-imido dicarbonimidic-diamine hydrochloride (PS-15), were tested in combination with a series of antimalarial drugs for synergism against Plasmodium falciparum growing in erythrocytic culture. Four synergistic combinations were found: cycloguanil dapsone, WR99210-dapsone, proguanil-atovaquone, and PS-15-atovaquone. Cycloguanil-dapsone or WR99210-dapsone had a profound suppressive effect on the concentration of dTTP in parasites while that of dATP increased. Depletion of dTTP is consistent with cycloguanil or WR99210 inhibiting dihydrofolate reductase and dapsone inhibiting dihydropteroate synthase. For the combinations proguanil-atovaquone and PS-15-atovaquone, the levels of nucleoside triphosphates (NTPs) and dNTPs were generally suppressed, suggesting that inhibition is not through nucleotide pathways but probably through another metabolic mechanism(s). Combinations of two synergistic pairs of antimalarial drugs, (proguanil-atovaquone)-(cycloguanil-dapsone) and (PS-15-atovaquone)-(WR99210-dapsone), were tested, and it was found that NTPs and dNTPs decreased much more than for a single synergistic combination. Dual synergistic combinations could play an important role in the therapy of multidrug-resistant malaria, just as combination chemotherapy is used to treat cancer.
authors.affiliation: Department of Biochemistry, University of Sydney, NSW, Australia.
authors.forename: A E
authors.initials: AE
authors.lastname: Yeo
authors.forename: K K
authors.initials: KK
authors.lastname: Seymour
authors.forename: K H
authors.initials: KH
authors.lastname: Rieckmann
authors.forename: R I
authors.initials: RI
authors.lastname: Christopherson
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone; D002478:Cells, Cultured; D003570:Cytidine Triphosphate / Q000032:analysis; D003622:Dapsone / Q000494:pharmacology*; D004338:Drug Combinations; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D004912:Erythrocytes / Q000469:parasitology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000032:analysis; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014544:Uridine Triphosphate / Q000032:analysis
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D005493:Folic Acid Antagonists; D009285:Naphthoquinones; D003570:Cytidine Triphosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D003622:Dapsone; D014544:Uridine Triphosphate; D053626:Atovaquone