EFFECTS OF DUAL COMBINATIONS OF ANTIFOLATES WITH ATOVAQUONE OR DAPSONE ON NUCLEOTIDE LEVELS IN PLASMODIUM-FALCIPARUM

The triazine antifolates, cycloguanil and 4,-diamino-1,2-dihydro-2,2-d imethyl-1-[(2,4,5- trichlorophenoxy)propyloxy]-1,3,5-triazine hydrobro mide (WR99210), and their parent biguanide compounds, proguanil and ox y]-n-(l-methylethyl)-imidodicarbonimidic-diamine hydrochloride (PS-15) , were tested in combination with a series of antimalarial drugs for s ynergism against Plasmodium falciparum growing in erythrocytic culture . Four synergistic combinations were found: cycloguanil-dapsone, WR992 10-dapsone, proguanil-atovaquone, and PS-15-atovaquone. Cycloguanil-da psone or WR99210-dapsone had a profound suppressive effect on the conc entration of dTTP in parasites while that of dATP increased. Depletion of dTTP is consistent with cycloguanil or WR99210 inhibiting dihydrof olate reductase and dapsone inhibiting dihydropteroate synthase. For t he 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 pr obably through another metabolic mechanism(s). Combinations of two syn ergistic pairs of antimalarial drugs, (proguanil-atovaquone)-(cyclogua nil-dapsone) and (PS-15-atovaquone)-(WR99210-dapsone), were tested, an d it was found that NTPs and dNTPs decreased much more than for a sing le synergistic combination. Dual synergistic combinations could play a n important role in the therapy of multidrug-resistant malaria, just a s combination chemotherapy is used to treat cancer. (C) 1997 Elsevier Science Inc.