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Krekhno, Jessica Maria Christine

University of British Columbia

Mycobacterium tuberculosis and Mycobacterium abscessus are related bacteria which are responsible for deadly infectious diseases. M. tuberculosis, the causative agent of Tuberculosis, remains an urgent global health concern, causing over 1.5 million deaths annually. M. abscessus, while less virulent, leads to severe illness in individuals suffering from compounding conditions, primarily Cystic Fibrosis. With the concern of drug-resistance in both pathogens, new treatment methods are urgently needed. One potential drug target in M. tuberculosis is the cholesterol catabolic pathway. This pathway involves successive enzymatic steps that degrade cholesterol into central metabolites used in growth and infection. Not all steps of the pathway have been characterized. Furthermore, disruption of some steps results in a cholesterol-dependent toxicity that was recently linked to CoASH depletion. In contrast to our understanding of cholesterol catabolism in M. tuberculosis, there is very little known about this pathway in M. abscessus. M. abscessus is predicted to possess similar pathways for cholesterol and 4-androstenedione (4-AD) catabolism, although nothing is known about their roles in pathogenesis. In Chapter 2 of this thesis, I validated the two predicted steroid catabolic pathways in M. abscessus and demonstrated that they converge at an unusual point. Furthermore, I established that steroid metabolism is essential for intracellular growth of M. abscessus. Chapter 3 describes the characterization of a key CoASH biosynthetic enzyme from M. tuberculosis and how the accumulation of steroid metabolites can lead to CoASH depletion and thus toxicity. Finally, Chapter 4 defined the yet uncharacterized opening of cholesterol Ring D by EchA20 and proposed a mechanism for ring hydrolysis. Overall, this research expands our understanding about how mycobacterial pathogens break down cholesterol and the role of this degradation in pathogenesis. The insights gained provide a basis for designing novel therapeutics against both M. tuberculosis and M. abscessus.

Text

2023-12-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86993

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/