Understanding the essential components of non-stop ribosome rescue at the genomic and atomic level
Restricted (Penn State Only)
Author:
Marathe, Neeraja
Graduate Program:
Biochemistry, Microbiology, and Molecular Biology
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
March 01, 2024
Committee Members:
Ken Keiler, Chair & Dissertation Advisor Song Tan, Major Field Member Justin Pritchard, Outside Unit & Field Member Timothy Meredith, Major Field Member Emily Weinert, Major Field Member Santhosh Girirajan, Program Head/Chair
Ribosome rescue pathways are essential and conserved throughout bacteria. However, why this pathway is important for the physiology of bacteria is still unknown. The primary mechanism of ribosome rescue is via trans-translation. trans-translation can serve as a potential drug target because it is required for the viability of most pathogenic bacteria and is not found in metazoans. To understand why ribosome rescue is indispensable for all bacterial species, the essential interactions and substrate specificity required for ribosome rescue need to be answered. The role of ribosome rescue can be investigated using small molecules known to target the trans-translation pathway. High-throughput screening identified small molecule inhibitors of trans-translation that have broad-spectrum antibiotic activity. The findings in this dissertation identify molecular targets of one such trans-translation inhibitor which in turn points out the essential interactions needed for ribosome rescue. The findings also show that the different inhibitors of trans-translation have different effects on non-stop ribosomes thereby opening up possibilities of understanding different aspects of ribosome rescue. This in turn can be exploited to make more effective drugs that specifically target this pathway and help curb the ever-growing problem of antibiotic resistance.
