Malaria remains the most important parasitic disease in the world, affecting hundreds of millions of people and killing almost 1 million each year. Anti-malarial drugs remain the mainstay of malaria management, but the emergence and spread of resistance to these drugs is of grave concern. It is apparent that for the foreseeable future we need to feed a robust pipeline with compounds that either overcome drug resistance or target novel physiological processes vital for the parasite. Towards this goal, our laboratory has shown the mitochondrion of malaria parasites to be highly diminished and divergent from its mammalian counterpart, and has validated its physiology as a target for anti-malarial drugs such as atovaquone. We have demonstrated selective inhibition of parasite mitochondrial electron transport chain (mtETC) at the cytochrome bc1 complex by at least 3 additional chemical classes of compounds under development as antimalarials. We showed that a critical function of mtETC in Plasmodium falciparum blood stages was to serve as an electron disposal system for the mitochondrially located dihydroorotate dehydrogenase (DHODH), thereby supporting the essential pyrimidine biosynthesis. Among several implications of this finding, it provided further validation of parasite DHODH as a target for anti-malarial drug development, an effort underway by several groups. Our initial investigations of the ATP synthase complex, ubiquinone-requiring mitochondrial dehydrogenase, and enzymes and architecture of tricarboxylic acid (TCA) metabolism all suggest unusual aspects of mitochondrial functions in malaria parasites. Our results also suggest essential nature of some of these processes with the possibility that they could serve as potential targets for drug development. With greatly improved tools and technology developed over the recent years, we propose to investigate these functions in greater details with the hope that this knowledge could guide search for novel strategies to develop anti-malarial drugs. We will combine the power of genetic manipulation and metabolomic analysis in this investigation to assess contributions made by the two branches of the unusual TCA metabolism of the parasite. We will also examine the role mitochondrial processes during in vivo infection as well as in sexual and mosquito stages of malaria parasites. Finally, we will investigate the unusual ATP synthase as well as mitochondrial respiratory complexes to understand their functional significance and impact on parasite physiology. These studies have the potential to be highly valuable in developing strategies for chemotherapeutic intervention affecting validated targets of malaria parasites.

Public Health Relevance

There is a dire need to develop new anti-malarial drugs that target novel physiological processes of malaria parasites. The unusual mitochondrion of the malaria parasite represents an attractive target that has been validated for anti-malarial drug action. This project aims to derive deeper understanding of additional unusual features of the parasite mitochondrion with a view to eventually guide further strategies for drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028398-25
Application #
8665865
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcgugan, Glen C
Project Start
1989-07-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
25
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Jenkins, Bethany J; Daly, Thomas M; Morrisey, Joanne M et al. (2016) Characterization of a Plasmodium falciparum Orthologue of the Yeast Ubiquinone-Binding Protein, Coq10p. PLoS One 11:e0152197
Ke, Hangjun; Morrisey, Joanne M; Qu, Shiwei et al. (2016) Caged Garcinia xanthones: a novel chemical scaffold with potent antimalarial activity. Antimicrob Agents Chemother :
Stickles, Allison M; Smilkstein, Martin J; Morrisey, Joanne M et al. (2016) Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria. Antimicrob Agents Chemother 60:4853-9
Stickles, Allison M; de Almeida, Mariana Justino; Morrisey, Joanne M et al. (2015) Subtle changes in endochin-like quinolone structure alter the site of inhibition within the cytochrome bc1 complex of Plasmodium falciparum. Antimicrob Agents Chemother 59:1977-82
Ke, Hangjun; Lewis, Ian A; Morrisey, Joanne M et al. (2015) Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle. Cell Rep 11:164-74
Miley, Galen P; Pou, Sovitj; Winter, Rolf et al. (2015) ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria. Antimicrob Agents Chemother 59:5555-60
Stickles, Allison M; Ting, Li-Min; Morrisey, Joanne M et al. (2015) Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy. Am J Trop Med Hyg 92:1195-201
Rajgor, D D; Gogtay, N J; Kadam, V S et al. (2014) Antirelapse Efficacy of Various Primaquine Regimens for Plasmodium vivax. Malar Res Treat 2014:347018
Ke, Hangjun; Sigala, Paul A; Miura, Kazutoyo et al. (2014) The heme biosynthesis pathway is essential for Plasmodium falciparum development in mosquito stage but not in blood stages. J Biol Chem 289:34827-37
Nilsen, Aaron; Miley, Galen P; Forquer, Isaac P et al. (2014) Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers. J Med Chem 57:3818-34

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