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Naphthoquinones: Atovaquone, and Other Antimalarials Targeting Mitochondrial Functions

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Treatment and Prevention of Malaria

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Mitochondria in malaria parasites are highly divergent from their counterparts in mammalian hosts. This degree of divergence underlies the validity of mitochondrial functions as targets for antimalarial drugs. The mitochondrial electron transport chain (mtETC) at the cytochrome bc 1 complex is selectively inhibited in malaria parasites by atovaquone. Proguanil, the synergistic partner of atovaquone, appears to target an alternative pathway that generates electropotential across the inner membrane of parasite mitochondria. However, the rapid emergence of atovaquone-resistance mutations effectively negates the synergistic effect of proguanil. New antimalarials targeting the mtETC with reduced propensity for resistance development could overcome this challenge. A critical function of the mtETC is to serve mitochondrially located dihydroorotate dehydrogensae (DHODH), an enzyme of the pyrimidine biosynthesis pathway. Compounds with selective activity against parasite DHODH are under development as potential new antimalarials. Recent studies on unusual tricarboxylic acid metabolism and ATP synthase structure point to additional opportunities for investigations aimed to identify other selective inhibitors.

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Acknowledgments

I thank colleagues and students in the Center for Molecular Parasitology at Drexel University College of Medicine for discussions and dynamism. I am also grateful for funding from the US National Institutes of Health (Grant number: AI028398) and Medicines for Malaria Venture.

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Authors and Affiliations

  1. Department of Microbiology and Immunology Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, 19129, USA

    Akhil B. Vaidya

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  1. Akhil B. Vaidya
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Correspondence to Akhil B. Vaidya .

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Editors and Affiliations

  1. Centre for Infection, Div. Cellular & Molecular Medicine, St. George's University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom

    Henry M. Staines

  2. Medical School, Dept. Infectious Diseases, St. George´s Hospital, Cranmer Terrace, London, SW17 0RE, United Kingdom

    Sanjeev Krishna

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Vaidya, A.B. (2011). Naphthoquinones: Atovaquone, and Other Antimalarials Targeting Mitochondrial Functions. In: Staines, H., Krishna, S. (eds) Treatment and Prevention of Malaria. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0346-0480-2_7

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