Acetyl-CoA Production Inside and Outside of the Mitochondrion is Essential for Plasmodium falciparum During Asexual Red Blood Cell and Sexual Stage Development
Restricted (Penn State Only)
Author:
Munro, Justin
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
June 20, 2022
Committee Members:
Andrew Patterson, Outside Unit & Field Member Scott Showalter, Major Field Member Manuel Llinas, Chair & Dissertation Advisor Philip Bevilacqua, Major Field Member Philip Bevilacqua, Program Head/Chair
Malaria is an immensely problematic disease that is caused by eukaryotic protozoan parasites of the genus Plasmodium. While many treatments for the disease currently exist, additional barriers such as drug resistance are hampering the progress of current malaria elimination efforts. Therefore, further research into new drug targets and antimalarial compounds is necessary to provide novel tools to combat malaria. This dissertation aims to describe a small set of research efforts to use Plasmodium falciparum metabolomics experiments to further inform pharmacological studies, drug target studies, and conditional gene expression studies. Specifically, the work described in this dissertation will describe methods to critically target acetyl-CoA synthetase with drugs through cytosolic processes and will identify an essential process of acetyl-CoA generation within the mitochondrion. Further, the metabolic effects of several conditional expression drugs will be investigated upon incubation of the Plasmodium falciparum parasites in the presence of the respective compounds. The results of these studies are not only necessary to allow early-stage candidate antimalarial compounds to enter clinical trials, but also to identify essential biochemical processes to the parasites that can be used to generate new antimalarial compounds with novel modes of action in the future.
