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ORCID

http://orcid.org/0000-0002-2004-1278

Date of Award

Summer 8-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Malaria is estimated to be responsible for over half of all deaths throughout human history. The protozoan parasite Plasmodium falciparum is the deadliest form of malaria, contributing to the largest share of the 200 million infections and nearly 1 million malarial deaths annually. The most vulnerable of our population including pregnant mothers, young children, and the immune compromised are most susceptible to this global health threat. Treatment and prevention of this disease remains an uphill battle, despite major advances in modern healthcare. This is underscored by the fact that resistance has emerged for every currently available antimalarial. The desperate need for effective therapeutics requires the investigation of novel therapeutic targets. We approach this problem by identifying metabolic control mechanisms that are present in malaria parasites but distinct from the human host. Specifically, we identified novel metabolic regulation and non-metabolic roles of glycolytic enzymes, including phosphofructokinase (PFK9, PF3D7_0915400) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH, PF3D7_1462800) in P. falciparum. These roles were identified through a combination of metabolic perturbations, including the use of metabolic inhibitors to establish resistance to a metabolic block and allowing spontaneous genetic suppression of resistance genotypes that result from fitness costs. Therefore, our findings not only have direct implications for understanding antimalarial drug resistance but also the overall metabolic plasticity of P. falciparum. Beyond our identification of novel roles and regulation of glycolytic enzymes in P. falciparum, we evaluated the practicality of targeting glycolysis for antimalarial development. The highly conserved nature of glycolysis between host and pathogen provokes strong consideration of the toxic effects of targeting this pathway. We confirmed a high tolerance for disruption of the glycolytic enzyme enolase in the mammalian host and the ability of enolase inhibitors to prevent parasite growth in vitro. In our effort to understand the toxic effects of acute glycolytic disruption, we defined the metabolic signature of enolase inhibition and mechanism of toxicity in red blood cells of the mammalian host. These data led to the identification of potential host detoxifying strategies that may increase a therapeutic window when targeting glycolysis for the treatment of malaria. Together, these findings open new paths investigating metabolic regulatory mechanisms that may lead to promising drug targets.

Language

English (en)

Chair and Committee

Audrey R. Odom John

Committee Members

Michael G. Caparon, Allan Doctor, Tamara L. Doering, Daniel E. Goldberg,

Comments

Permanent URL: https://doi.org/10.7936/yrbs-wp38

Available for download on Tuesday, August 15, 2119

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