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

Moritz, Elizabeth M.

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https://hdl.handle.net/2142/17030 Copy

Description

Title

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

Author(s)

Moritz, Elizabeth M.

Issue Date

2010-08-31T20:29:51Z

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul J.

Doctoral Committee Chair(s)

Hergenrother, Paul J.

Committee Member(s)

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

Department of Study

Microbiology

Discipline

Microbiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

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

Abstract

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.

Graduation Semester

2010-08

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

Copyright and License Information

Copyright 2010 Elizabeth Margaret Moritz

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