The prevalence of toxin-antitoxin systems and their tractability as novel antimicrobial targets

Large, low copy number plasmids, such as those harboring antibiotic resistance genes, often possess plasmid maintenance systems to ensure their persistence and inheritance in a bacterial population. One example is the proteic toxin-antitoxin (TA) system, consisting of a toxin and an antitoxin encoded in a single operon. When expressed, the antitoxin binds to and neutralizes the toxin. However, if during cell division a plasmid-free daughter cell arises, the labile antitoxin is rapidly degraded, freeing the toxin to kill the cell. If TA systems are prevalent and functional in clinically relevant bacteria, they could be exploited as a novel antimicrobial strategy: a small molecule capable of relieving the neutralizing effect of the antitoxin would free the toxin to kill the cell. This thesis research has, in part, focused on defining the prevalence of TA systems in clinical isolates of vancomycin-resistant enterococci and methicillin-resistant S. aureus to validate TA systems as an antibacterial target. Two TA systems, Axe-Txe and RelBE, were found to be common among the pathogenic bacteria surveyed and were therefore further investigated. A cell-based high-throughput assay was developed to screen for small molecules that induce toxin-dependent cell death in E. coli expressing RelBE. Additionally, mechanistic studies were performed to determine the mode of action by which the Txe toxin causes cell death.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2010

Author dc:creator

• Moritz, Elizabeth M.

Contributors dc:contributor

• Hergenrother, Paul J.
• Slauch, James M.
• Wilson, Brenda A.
• Farrand, Stephen K.

• Vancomycin-resistant enterococci (VRE)
• Methicillin-resistant Staphylococcus aureus (MRSA)
• relBE
• toxin-antitoxin
• Axe-Txe

Statement dc:rights

• Copyright 2010 Elizabeth Margaret Moritz

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/17030

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/17030