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Structure, Function, and Inhibition of Peptidoglycan O-Acetyltransferase A from Staphylococcus aureus

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Title: Structure, Function, and Inhibition of Peptidoglycan O-Acetyltransferase A from Staphylococcus aureus
Author: Jones, Carys S.
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Clarke, Anthony J.
Abstract: Peptidoglycan (PG) is an essential cell wall component of most bacteria and serves to resist turgor pressure and protect the cell. Many bacteria modify their PG layer post-biosynthetically, which can have implications on pathogenicity. O-Acetylation of PG is an important modification utilized by both Gram-positive and Gram-negative bacteria to regulate autolysins and provide resistance to host-immune attack by lysozyme. This modification commonly occurs in several notable pathogens, including Staphylococcus aureus. In Gram-positive bacteria, PG O-acetylation is accomplished by a single dual domain enzyme, O acetyltransferase A (OatA). As a recognized virulence factor, OatA is of interest in the development of novel strategies to overcome antimicrobial resistance. In this study, S. aureus OatA was subjected to a large high-throughput screen to identify and characterize inhibitors of the enzyme. To improve our understanding of the PG O-acetylation system as a whole, the structures and functions of both domains of S. aureus OatA were also investigated. The topology of the N-terminal transmembrane domain was determined, and putative functional residues were investigated with in vivo and in vitro mutagenesis studies. A model for its mechanism and interaction with the C-terminal domain is proposed. Furthermore, the crystal structure of the C-terminal domain of S. aureus OatA is presented alongside an analysis of its catalytic mechanism.
URI: http://hdl.handle.net/10214/17946
Date: 2020-05
Rights: Attribution-NoDerivatives 4.0 International
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Attribution-NoDerivatives 4.0 International Except where otherwise noted, this item's license is described as Attribution-NoDerivatives 4.0 International