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Special Issue "Toxin-antitoxin (TA) systems"

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: 30 April 2019

Special Issue Editor

Guest Editor
Dr. Sabine Brantl

Matthias-Schleiden-Institut, AG Bakteriengenetik, Friedrich-Schiller-Universität Jena, Philosophenweg 12, 07743 Jena, Germany
Website | E-Mail
Phone: +49-3641 949570

Special Issue Information

Dear Colleagues,

Bacterial toxin–antitoxin (TA) systems are ubiquitous modules found in almost all sequenced bacterial genomes. They consist of two genes, one encoding a stable toxin, whose overexpression kills the cell or causes growth stasis, and the other encoding an unstable antitoxin that neutralizes toxin action. To date, four different TA systems are known. Whereas in type I and III TA systems, the antitoxin is a small RNA, in type II and IV systems, toxins and antitoxins are proteins. In addition, two single instances have been reported as type V and type VI TA modules, both with proteinaceous toxins and antitoxins. Toxins are small polypeptides that use a variety of molecular mechanisms to inhibit essential cellular processes, such as cell division, DNA replication, translation or membrane integrity. Although toxin targets are known in many instances, their identification is still a challenging issue.

So far, three major biological functions of TA modules have been discovered, post-segregational killing ("plasmid addiction"), abortive infection (bacteriophage immunity through altruistic suicide), and persister formation (antibiotic tolerance through dormancy). Other functions have been proposed, but have not yet been experimentally supported. Many genomes carry multiple TA systems that frequently employ different mechanisms of growth inhibition.

This Special Issue will focus on the discovery and biological functions of new TA systems of all types, the characterization of toxins and the identification of their cellular targets, as well as regulatory mechanisms used by the corresponding antitoxins.

Dr. Sabine Brantl
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Toxin–antitoxin systems
  • Toxins
  • Antitoxins
  • Postsegregational killing
  • Abortive infection
  • Persister formation

Published Papers (7 papers)

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Research

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Open AccessArticle Pseudomonas putida Responds to the Toxin GraT by Inducing Ribosome Biogenesis Factors and Repressing TCA Cycle Enzymes
Received: 21 December 2018 / Revised: 29 January 2019 / Accepted: 7 February 2019 / Published: 9 February 2019
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Abstract
The potentially self-poisonous toxin-antitoxin modules are widespread in bacterial chromosomes, but despite extensive studies, their biological importance remains poorly understood. Here, we used whole-cell proteomics to study the cellular effects of the Pseudomonas putida toxin GraT that is known to inhibit growth and [...] Read more.
The potentially self-poisonous toxin-antitoxin modules are widespread in bacterial chromosomes, but despite extensive studies, their biological importance remains poorly understood. Here, we used whole-cell proteomics to study the cellular effects of the Pseudomonas putida toxin GraT that is known to inhibit growth and ribosome maturation in a cold-dependent manner when the graA antitoxin gene is deleted from the genome. Proteomic analysis of P. putida wild-type and ΔgraA strains at 30 °C and 25 °C, where the growth is differently affected by GraT, revealed two major responses to GraT at both temperatures. First, ribosome biogenesis factors, including the RNA helicase DeaD and RNase III, are upregulated in ΔgraA. This likely serves to alleviate the ribosome biogenesis defect of the ΔgraA strain. Secondly, proteome data indicated that GraT induces downregulation of central carbon metabolism, as suggested by the decreased levels of TCA cycle enzymes isocitrate dehydrogenase Idh, α-ketoglutarate dehydrogenase subunit SucA, and succinate-CoA ligase subunit SucD. Metabolomic analysis revealed remarkable GraT-dependent accumulation of oxaloacetate at 25 °C and a reduced amount of malate, another TCA intermediate. The accumulation of oxaloacetate is likely due to decreased flux through the TCA cycle but also indicates inhibition of anabolic pathways in GraT-affected bacteria. Thus, proteomic and metabolomic analysis of the ΔgraA strain revealed that GraT-mediated stress triggers several responses that reprogram the cell physiology to alleviate the GraT-caused damage. Full article
(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)
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Open AccessArticle Toxin ζ Reduces the ATP and Modulates the Uridine Diphosphate-N-acetylglucosamine Pool
Received: 4 December 2018 / Revised: 21 December 2018 / Accepted: 4 January 2019 / Published: 9 January 2019
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Abstract
Toxin ζ expression triggers a reversible state of dormancy, diminishes the pool of purine nucleotides, promotes (p)ppGpp synthesis, phosphorylates a fraction of the peptidoglycan precursor uridine diphosphate-N-acetylglucosamine (UNAG), leading to unreactive UNAG-P, induces persistence in a reduced subpopulation, and sensitizes cells to different [...] Read more.
Toxin ζ expression triggers a reversible state of dormancy, diminishes the pool of purine nucleotides, promotes (p)ppGpp synthesis, phosphorylates a fraction of the peptidoglycan precursor uridine diphosphate-N-acetylglucosamine (UNAG), leading to unreactive UNAG-P, induces persistence in a reduced subpopulation, and sensitizes cells to different antibiotics. Here, we combined computational analyses with biochemical experiments to examine the mechanism of toxin ζ action. Free ζ toxin showed low affinity for UNAG. Toxin ζ bound to UNAG hydrolyzed ATP·Mg2+, with the accumulation of ADP, Pi, and produced low levels of phosphorylated UNAG (UNAG-P). Toxin ζ, which has a large ATP binding pocket, may temporally favor ATP binding in a position that is distant from UNAG, hindering UNAG phosphorylation upon ATP hydrolysis. The residues D67, E116, R158 and R171, involved in the interaction with metal, ATP, and UNAG, were essential for the toxic and ATPase activities of toxin ζ; whereas the E100 and T128 residues were partially dispensable. The results indicate that ζ bound to UNAG reduces the ATP concentration, which indirectly induces a reversible dormant state, and modulates the pool of UNAG. Full article
(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)
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Open AccessArticle Identification of Three Type II Toxin-Antitoxin Systems in Streptococcus suis Serotype 2
Toxins 2018, 10(11), 467; https://doi.org/10.3390/toxins10110467
Received: 22 October 2018 / Revised: 6 November 2018 / Accepted: 7 November 2018 / Published: 13 November 2018
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Abstract
Type II toxin-antitoxin (TA) systems are highly prevalent in bacterial genomes and have been extensively studied. These modules involve in the formation of persistence cells, the biofilm formation, and stress resistance, which might play key roles in pathogen virulence. SezAT and yefM-yoeB TA [...] Read more.
Type II toxin-antitoxin (TA) systems are highly prevalent in bacterial genomes and have been extensively studied. These modules involve in the formation of persistence cells, the biofilm formation, and stress resistance, which might play key roles in pathogen virulence. SezAT and yefM-yoeB TA modules in Streptococcus suis serotype 2 (S. suis 2) have been studied, although the other TA systems have not been identified. In this study, we investigated nine putative type II TA systems in the genome of S. suis 2 strain SC84 by bioinformatics analysis and identified three of them (two relBE loci and one parDE locus) that function as typical type II TA systems. Interestingly, we found that the introduction of the two RelBE TA systems into Escherichia coli or the induction of the ParE toxin led to cell filamentation. Promoter activity assays indicated that RelB1, RelB2, ParD, and ParDE negatively autoregulated the transcriptions of their respective TA operons, while RelBE2 positively autoregulated its TA operon transcription. Collectively, we identified three TA systems in S. suis 2, and our findings have laid an important foundation for further functional studies on these TA systems. Full article
(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)
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Open AccessArticle HigB Reciprocally Controls Biofilm Formation and the Expression of Type III Secretion System Genes through Influencing the Intracellular c-di-GMP Level in Pseudomonas aeruginosa
Toxins 2018, 10(11), 424; https://doi.org/10.3390/toxins10110424
Received: 20 September 2018 / Revised: 21 October 2018 / Accepted: 22 October 2018 / Published: 24 October 2018
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Abstract
Toxin-antitoxin (TA) systems play important roles in bacteria persister formation. Increasing evidence demonstrate the roles of TA systems in regulating virulence factors in pathogenic bacteria. The toxin HigB in Pseudomonas aeruginosa contributes to persister formation and regulates the expression of multiple virulence factors [...] Read more.
Toxin-antitoxin (TA) systems play important roles in bacteria persister formation. Increasing evidence demonstrate the roles of TA systems in regulating virulence factors in pathogenic bacteria. The toxin HigB in Pseudomonas aeruginosa contributes to persister formation and regulates the expression of multiple virulence factors and biofilm formation. However, the regulatory mechanism remains elusive. In this study, we explored the HigB mediated regulatory pathways. We demonstrate that HigB decreases the intracellular level of c-di-GMP, which is responsible for the increased expression of the type III secretion system (T3SS) genes and repression of biofilm formation. By analyzing the expression levels of the known c-di-GMP metabolism genes, we find that three c-di-GMP hydrolysis genes are up regulated by HigB, namely PA2133, PA2200 and PA3825. Deletion of the three genes individually or simultaneously diminishes the HigB mediated regulation on the expression of T3SS genes and biofilm formation. Therefore, our results reveal novel functions of HigB in P. aeruginosa. Full article
(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)
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Open AccessArticle The Streptococcus pneumoniae yefM-yoeB and relBE Toxin-Antitoxin Operons Participate in Oxidative Stress and Biofilm Formation
Received: 9 August 2018 / Revised: 3 September 2018 / Accepted: 13 September 2018 / Published: 18 September 2018
Cited by 2 | PDF Full-text (2001 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Type II (proteic) toxin-antitoxin systems (TAs) are widely distributed among bacteria and archaea. They are generally organized as operons integrated by two genes, the first encoding the antitoxin that binds to its cognate toxin to generate a harmless protein–protein complex. Under stress conditions, [...] Read more.
Type II (proteic) toxin-antitoxin systems (TAs) are widely distributed among bacteria and archaea. They are generally organized as operons integrated by two genes, the first encoding the antitoxin that binds to its cognate toxin to generate a harmless protein–protein complex. Under stress conditions, the unstable antitoxin is degraded by host proteases, releasing the toxin to achieve its toxic effect. In the Gram-positive pathogen Streptococcus pneumoniae we have characterized four TAs: pezAT, relBE, yefM-yoeB, and phD-doc, although the latter is missing in strain R6. We have assessed the role of the two yefM-yoeB and relBE systems encoded by S. pneumoniae R6 by construction of isogenic strains lacking one or two of the operons, and by complementation assays. We have analyzed the phenotypes of the wild type and mutants in terms of cell growth, response to environmental stress, and ability to generate biofilms. Compared to the wild-type, the mutants exhibited lower resistance to oxidative stress. Further, strains deleted in yefM-yoeB and the double mutant lacking yefM-yoeB and relBE exhibited a significant reduction in their ability for biofilm formation. Complementation assays showed that defective phenotypes were restored to wild type levels. We conclude that these two loci may play a relevant role in these aspects of the S. pneumoniae lifestyle and contribute to the bacterial colonization of new niches. Full article
(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)
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Open AccessArticle Bacillus subtilis Type I antitoxin SR6 Promotes Degradation of Toxin yonT mRNA and Is Required to Prevent Toxic yoyJ Overexpression
Received: 18 January 2018 / Revised: 30 January 2018 / Accepted: 4 February 2018 / Published: 7 February 2018
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Abstract
yonT/SR6 is the second type I toxin-antitoxin (TA) system encoded on prophage SPβ in the B. subtilis chromosome. The yonT ORF specifying a 58 aa toxin is transcribed on a polycistronic mRNA under control of the yonT promoter. The antitoxin SR6 is [...] Read more.
yonT/SR6 is the second type I toxin-antitoxin (TA) system encoded on prophage SPβ in the B. subtilis chromosome. The yonT ORF specifying a 58 aa toxin is transcribed on a polycistronic mRNA under control of the yonT promoter. The antitoxin SR6 is a 100 nt antisense RNA that overlaps yonT at its 3′ end and the downstream gene yoyJ encoding a second, much weaker, toxin at its 5′ end. SR6 displays a half-life of >60 min, whereas yonT mRNA is less stable with a half-life of ≈8 min. SR6 is in significant excess over yonT mRNA except in minimal medium with glucose. It interacts with the 3′ UTR of yonT mRNA, thereby promoting its degradation by RNase III. By contrast, SR6 does not affect the amount or half-life of yoyJ mRNA. However, in its absence, a yoyJ overexpression plasmid could not be established in Bacillus subtilis suggesting that SR6 inhibits yoyJ translation by directly binding to its ribosome-binding site. While the amounts of both yonT RNA and SR6 were affected by vancomycin, manganese, heat-shock and ethanol stress as well as iron limitation, oxygen stress decreased only the amount of SR6. Full article
(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)
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Review

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Open AccessReview A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability
Toxins 2018, 10(12), 515; https://doi.org/10.3390/toxins10120515
Received: 6 November 2018 / Revised: 29 November 2018 / Accepted: 30 November 2018 / Published: 4 December 2018
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Abstract
Toxin-antitoxin (TA) systems are known to play various roles in physiological processes, such as gene regulation, growth arrest and survival, in bacteria exposed to environmental stress. Type II TA systems comprise natural complexes consisting of protein toxins and antitoxins. Each toxin and antitoxin [...] Read more.
Toxin-antitoxin (TA) systems are known to play various roles in physiological processes, such as gene regulation, growth arrest and survival, in bacteria exposed to environmental stress. Type II TA systems comprise natural complexes consisting of protein toxins and antitoxins. Each toxin and antitoxin participates in distinct regulatory mechanisms depending on the type of TA system. Recently, peptides designed by mimicking the interfaces between TA complexes showed its potential to activate the activity of toxin by competing its binding counterparts. Type II TA systems occur more often in pathogenic bacteria than in their nonpathogenic kin. Therefore, they can be possible drug targets, because of their high abundance in some pathogenic bacteria, such as Mycobacterium tuberculosis. In addition, recent bioinformatic analyses have shown that type III TA systems are highly abundant in the intestinal microbiota, and recent clinical studies have shown that the intestinal microbiota is linked to inflammatory diseases, obesity and even several types of cancer. We therefore focused on exploring the putative relationship between intestinal microbiota-related human diseases and type III TA systems. In this paper, we review and discuss the development of possible druggable materials based on the mechanism of type II and type III TA system. Full article
(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)
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