Leveraging the ΦX174 Protein Antibiotic to Study MraY Structure, Function, and Regulation

Author: Orta, Anna Karen

Year: 2024

Degree: Dissertation (Ph.D.)

Advisor: Clemons, William M.

Committee Members: Voorhees, Rebecca M.; Newman, Dianne K.; Bjorkman, Pamela J.; Clemons, William M.

Option: Biochemistry and Molecular Biophysics

DOI: 10.7907/ggr0-0n72

Abstract

The overuse of antibiotics has escalated the prevalence of bacterial resistance to existing treatments, posing a significant threat to global health. This rise in antimicrobial resistance (AMR) has spurred research into innovative therapeutic approaches. Among the most promising strategies is the use of viruses of bacteria for 'phage therapy'. This thesis delves into the interplay between antibacterial resistance and peptidoglycan biosynthesis, highlighting the pivotal role of the membrane protein MraY. We present the first structure of MraY from a pathogenic species, revealing its inhibition by the lysis protein from the bacteriophage ΦX174, protein E. Additionally, we analyze lipidic interactions with MraY, proposing a previously unexplored allosteric feedback mechanism for regulating its enzymatic activity. Building on these insights, we expand the application of protein E to non-native hosts, offering new avenues for the development of targeted antibiotic interventions. This work not only advances our understanding of the structural and functional dynamics of MraY but also paves the way for novel antibacterial strategies.

Files