A mechanism for the synergistic antimalarial action of atovaquone and proguanil

A combination of atovaquone and proguanil has been found to be quite effect ive in treating malaria, with little evidence of the emergence of resistanc e when atovaquone nas used as a single agent. We have examined possible mec hanisms for the synergy between these two drugs. While proguanil by itself had no effect on electron transport or mitochondrial membrane potential (De lta Psi(m)), it significantly enhanced the ability of atovaquone to collaps e Delta Psi(m) when used in combination. This enhancement was observed at p harmacologically achievable doses. Proguanil acted as a biguanide rather th an as its metabolite cycloguanil (a parasite dihydrofolate reductase [DHFR] inhibitor) to enhance the atovaquone effect; another DHFR inhibitor, pyrim ethamine, also had no enhancing effect. Proguanil-mediated enhancement was specific for atovaquone, since the effects of other mitochondrial electron transport inhibitors, such as myxothiazole and antimycin, were not altered by inclusion of proguanil, Surprisingly, proguanil did not enhance the abil ity of atovaquone to inhibit mitochondrial electron transport in malaria pa rasites. These results suggest that proguanil in its prodrug form acts in s ynergy with atovaquone by lowering the effective concentration at which ato vaquone collapses Delta Psi(m) in malaria parasites. This could explain the paradoxical success of the atovaquone-proguanil combination even in region s where proguanil alone is ineffective due to resistance. The results also suggest that the atovaquone-proguanil combination mag act as a site-specifi c uncoupler of parasite mitochondria in a selective manner.