Identification of biogenesis factors and drug targets in the apicoplast proteome of malaria parasites
Abstract/Contents
- Abstract
- Malaria, caused by apicomplexan parasites of the genus Plasmodium, is a devastating disease of global importance, with over 200 million yearly cases leading to more than 400,000 annual deaths. Emerging resistance to current frontline treatments necessitates continued identification of new, parasite-specific drug targets with mechanisms-of-action orthogonal to current treatments. One key source of novel targets is the apicoplast, a nonphotosynthetic, 4-membraned plastid that performs critical metabolic functions throughout the parasite life cycle. Apicoplast maintenance and biogenesis are essential processes and validated drug targets, but our limited molecular understanding of apicoplast organelle biology has hindered the discovery and development of chemotherapies that exploit these unique pathways for antiparasitic treatment. The work described in this dissertation addresses two aspects related to identifying and drugging apicoplast biogenesis factors. First, the full complement of apicoplast-localized proteins is poorly characterized, and this lack of a reliable apicoplast proteome has limited our ability to mechanistically interrogate the most novel aspects of apicoplast biogenesis. Using a combination of proximity biotinylation-based mass spectrometry and machine learning, I report a high-confidence apicoplast proteome that is rich in novel and essential functions. Critically, many of these novel proteins are parasite-specific and will likely yield new insights into mechanisms of apicoplast biogenesis. Second, even given a high-confidence proteome, methods for prioritizing the most promising candidates for drug discovery efforts are limited. This is especially so given the context that some inhibitors of apicoplast biogenesis cause an undesirable "delayed-death" phenotype resulting in a slow onset-of-action that limits the clinical utility of these drugs. Using a chemical biology approach designed to selectively disrupt apicoplast protein import, I show that this particular biogenesis pathway appears to avoid the delayed-death phenotype. This suggests that targeting apicoplast protein import may yield clinically useful antimalarials and that protein-level conditional tools are valuable resources for characterizing apicoplast biogenesis pathways. Altogether, the results of these studies will facilitate detailed investigation of the mechanisms and chemical inhibition of apicoplast biogenesis.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Boucher, Michael Joseph |
|---|---|
| Degree supervisor | Yeh, Ellen |
| Thesis advisor | Yeh, Ellen |
| Thesis advisor | Boothroyd, John C |
| Thesis advisor | Carette, Jan, 1971- |
| Thesis advisor | Grossman, Arthur (Arthur R.) |
| Thesis advisor | Kirkegaard, Karla |
| Degree committee member | Boothroyd, John C |
| Degree committee member | Carette, Jan, 1971- |
| Degree committee member | Grossman, Arthur (Arthur R.) |
| Degree committee member | Kirkegaard, Karla |
| Associated with | Stanford University, Department of Microbiology and Immunology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Michael Joseph Boucher. |
|---|---|
| Note | Submitted to the Department of Microbiology and Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Michael Joseph Boucher
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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