ORCID
https://orcid.org/0000-0001-7212-4262
Date of Award
Spring 2025
Language
English
Embargo Period
5-1-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
College/School/Department
Department of Biomedical Sciences
Program
Biomedical Sciences
First Advisor
Anil Ojha
Committee Members
Randall Morse, Richard Cole, Gabriele Fuchs, Pallavi Ghosh, Todd Gray
Keywords
Non-tuberculosis mycobacteria, antibiotic resistance, ribosome hibernation, stringent response, nutrient starvation
Subject Categories
Amino Acids, Peptides, and Proteins | Bacterial Infections and Mycoses | Other Chemicals and Drugs | Respiratory Tract Diseases | Therapeutics
Abstract
Non-tuberculosis mycobacteria (NTM) represent a diverse repertoire of species, most of which are ubiquitous in the environment. Some NTM species, such as Mycobacterium abscessus, can cause life-threatening infections in people with underlying medical conditions. The clinical incidence of such infections is on the rise, posing an emerging threat to public health. M. abscessus is characterized by intrinsic and acquired antibiotic resistance, complicating treatment strategies. Most chemotherapeutic approaches for M. abscessus infection target the bacterial ribosome, necessitating a better understanding of the physiological processes which confer this resistance. Multiple mycobacterial species respond to zinc-limiting conditions by inducing remodeling and hibernation of 70S ribosomes. Ribosome remodeling in this context refers to the replacement of zinc-binding proteins on the ribosomal surface with their paralogues. Ribosome hibernation involves binding of mycobacterial protein Y (Mpy) to the 30S subunit near the inter-subunit interface of the 70S ribosome encompassing the decoding center, thereby inactivating the ribosome in a stable state. We hypothesize that Mpy-dependent ribosome hibernation drives resistance to a clinically relevant aminoglycoside in M. abscessus, amikacin. We perform a systematic analysis of ribosome remodeling and hibernation in M. abscessus and determine the effect of ribosome hibernation on the susceptibility of M. abscessus to amikacin. Lastly, we offer new insights into the mycobacterial stringent response in a model in which Rsh surveils the amino acylation status of the tRNA during the first cycle of elongation to activate the stringent response. We note that this mechanism of Rsh activation is programmed to slow down upon induction of ribosome hibernation.
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Treen, Ryan, "Ribosome hibernation in Mycobacterium abscessus and its effect on antibiotic resistance" (2025). Electronic Theses & Dissertations (2024 - present). 242.
https://scholarsarchive.library.albany.edu/etd/242
Included in
Amino Acids, Peptides, and Proteins Commons, Bacterial Infections and Mycoses Commons, Other Chemicals and Drugs Commons, Respiratory Tract Diseases Commons, Therapeutics Commons
