Transcriptional Control of Toxin–Antitoxin Expression: Keeping Toxins Under Wraps Until the Time is Right

Kędzierska, Barbara; Hayes, Finbarr

doi:10.1002/9781119004813.ch42

Cited by 6 publications

(8 citation statements)

References 99 publications

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“…The antitoxin protein is not only the nemesis of its cognate toxin, but also the key factor that regulates transcription of the TA operon. The antitoxin is generally a DNA-binding protein that binds, albeit usually weakly, to the operator of the operon to repress its own transcription; whereas the toxin protein, which does not bind to the DNA upstream of the operon, usually serves as a co-repressor, by binding to the antitoxin protein and changing the conformation of the antitoxin-DNA complex, which lead to further repression (Bertram and Schuster, 2014 ; Hayes and Kêdzierska, 2014 ; Kędzierska and Hayes, 2016 ). In some cases, the molar ratio of antitoxin and toxin has great impact on the formation of the TA complex in terms of stoichiometries (Gelens et al, 2013 ).…”

Section: Antitoxins Neutralize the Lethality Of Their Cognate Toxins mentioning

confidence: 99%

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Chan

Espinosa

Yeo

2016

Front. Mol. Biosci.

119

121

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In their initial stages of discovery, prokaryotic toxin-antitoxin (TA) systems were confined to bacterial plasmids where they function to mediate the maintenance and stability of usually low- to medium-copy number plasmids through the post-segregational killing of any plasmid-free daughter cells that developed. Their eventual discovery as nearly ubiquitous and repetitive elements in bacterial chromosomes led to a wealth of knowledge and scientific debate as to their diversity and functionality in the prokaryotic lifestyle. Currently categorized into six different types designated types I–VI, type II TA systems are the best characterized. These generally comprised of two genes encoding a proteic toxin and its corresponding proteic antitoxin, respectively. Under normal growth conditions, the stable toxin is prevented from exerting its lethal effect through tight binding with the less stable antitoxin partner, forming a non-lethal TA protein complex. Besides binding with its cognate toxin, the antitoxin also plays a role in regulating the expression of the type II TA operon by binding to the operator site, thereby repressing transcription from the TA promoter. In most cases, full repression is observed in the presence of the TA complex as binding of the toxin enhances the DNA binding capability of the antitoxin. TA systems have been implicated in a gamut of prokaryotic cellular functions such as being mediators of programmed cell death as well as persistence or dormancy, biofilm formation, as defensive weapons against bacteriophage infections and as virulence factors in pathogenic bacteria. It is thus apparent that these antitoxins, as DNA-binding proteins, play an essential role in modulating the prokaryotic lifestyle whilst at the same time preventing the lethal action of the toxins under normal growth conditions, i.e., keeping the proverbial wolves at bay. In this review, we will cover the diversity and characteristics of various type II TA antitoxins. We shall also look into some interesting deviations from the canonical type II TA systems such as tripartite TA systems where the regulatory role is played by a third party protein and not the antitoxin, and a unique TA system encoding a single protein with both toxin as well as antitoxin domains.

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Section: Antitoxins Neutralize the Lethality Of Their Cognate Toxins mentioning

confidence: 99%

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Chan

Espinosa

Yeo

2016

Front. Mol. Biosci.

119

121

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“…TA genes were first described on plasmids resident in E. coli [169,170]. Much of the intervening research on elucidating the functional, biochemical and structural features of TA complexes has centered on the well-characterized E. coli K-12 laboratory strain [6,11,50,64,171,172,173,174,175,176,177,178,179,180] (Figure 2). However, E. coli species are very diverse genetically and encompass both commensal and pathogenic strains.…”

Section: Deciphering the Roles Of Ta Modules In Pathogenicitymentioning

confidence: 99%

Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis

2016

Self Cite

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Toxin-antitoxin (TA) cassettes are encoded widely by bacteria. The modules typically comprise a protein toxin and protein or RNA antitoxin that sequesters the toxin factor. Toxin activation in response to environmental cues or other stresses promotes a dampening of metabolism, most notably protein translation, which permits survival until conditions improve. Emerging evidence also implicates TAs in bacterial pathogenicity. Bacterial persistence involves entry into a transient semi-dormant state in which cells survive unfavorable conditions including killing by antibiotics, which is a significant clinical problem. TA complexes play a fundamental role in inducing persistence by downregulating cellular metabolism. Bacterial biofilms are important in numerous chronic inflammatory and infectious diseases and cause serious therapeutic problems due to their multidrug tolerance and resistance to host immune system actions. Multiple TAs influence biofilm formation through a network of interactions with other factors that mediate biofilm production and maintenance. Moreover, in view of their emerging contributions to bacterial virulence, TAs are potential targets for novel prophylactic and therapeutic approaches that are required urgently in an era of expanding antibiotic resistance. This review summarizes the emerging evidence that implicates TAs in the virulence profiles of a diverse range of key bacterial pathogens that trigger serious human disease.

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“…However, it has been found that the toxins of the T:A pairs can be useful as anti-virals [37,38] or anti-tumoral agents [39] rather than as antibacterials, with the exception of two reports dealing with the possible drugability of the Epsilon:Zeta TA system (below). Reviews on the drugability of these TA genetic modules have been published, and their advantages and pitfalls have been analyzed in detail [2,[40][41][42].…”

Section: Novel Targets and Novel Strategies To Fight Bacterial Infectmentioning

confidence: 99%

When Humans Met Superbugs: Strategies to Tackle Bacterial Resistances to Antibiotics

Bravo

Ruiz‐Cruz

Alkorta

et al. 2018

Biomolecular Concepts

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Bacterial resistance to antibiotics poses enormous health and economic burdens to our society, and it is of the essence to explore old and new ways to deal with these problems. Here we review the current status of multi-resistance genes and how they spread among bacteria. We discuss strategies to deal with resistant bacteria, namely the search for new targets and the use of inhibitors of protein-protein interactions, fragment-based methods, or modified antisense RNAs. Finally, we discuss integrated approaches that consider bacterial populations and their niches, as well as the role of global regulators that activate and/or repress the expression of multiple genes in fluctuating environments and, therefore, enable resistant bacteria to colonize new niches. Understanding how the global regulatory circuits work is, probably, the best way to tackle bacterial resistance.

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Transcriptional Control of Toxin–Antitoxin Expression: Keeping Toxins Under Wraps Until the Time is Right

Cited by 6 publications

References 99 publications

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Keeping the Wolves at Bay: Antitoxins of Prokaryotic Type II Toxin-Antitoxin Systems

Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis

When Humans Met Superbugs: Strategies to Tackle Bacterial Resistances to Antibiotics

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