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Antimicrobial Agents and Chemotherapy, June 1999, p. 1334-1339, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil

Indresh K. Srivastavadagger and Akhil B. Vaidya*

Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania

Received 6 January 1999/Returned for modification 2 March 1999/Accepted 16 March 1999

A combination of atovaquone and proguanil has been found to be quite effective in treating malaria, with little evidence of the emergence of resistance when atovaquone was used as a single agent. We have examined possible mechanisms for the synergy between these two drugs. While proguanil by itself had no effect on electron transport or mitochondrial membrane potential (Delta Psi m), it significantly enhanced the ability of atovaquone to collapse Delta Psi m when used in combination. This enhancement was observed at pharmacologically achievable doses. Proguanil acted as a biguanide rather than as its metabolite cycloguanil (a parasite dihydrofolate reductase [DHFR] inhibitor) to enhance the atovaquone effect; another DHFR inhibitor, pyrimethamine, 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 ability of atovaquone to inhibit mitochondrial electron transport in malaria parasites. These results suggest that proguanil in its prodrug form acts in synergy with atovaquone by lowering the effective concentration at which atovaquone collapses Delta Psi m in malaria parasites. This could explain the paradoxical success of the atovaquone-proguanil combination even in regions where proguanil alone is ineffective due to resistance. The results also suggest that the atovaquone-proguanil combination may act as a site-specific uncoupler of parasite mitochondria in a selective manner.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, 2900 Queen La., Philadelphia, PA 19129. Phone: (215) 991-8557. Fax: (215) 843-4152. E-mail: vaidyaa{at}mcphu.edu.

dagger Present address: Chiron Corporation, Emeryville, Calif.

Antimicrobial Agents and Chemotherapy, June 1999, p. 1334-1339, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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