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Toxin-antitoxin (TA) systems

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

Deadline for manuscript submissions: closed (30 April 2019) | Viewed by 56781

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Dr. Sabine Brantl

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Matthias-Schleiden-Institut, AG Bakteriengenetik, Friedrich-Schiller-Universität Jena, Philosophenweg 12, 07743 Jena, Germany

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

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Keywords

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

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Published Papers (11 papers)

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Research

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15 pages, 3691 KiB

Open AccessArticle

A Short Peptide Derived from the ZorO Toxin Functions as an Effective Antimicrobial

by Yuichi Otsuka, Tomohiro Ishikawa, Chisato Takahashi and Michiaki Masuda

Toxins 2019, 11(7), 392; https://doi.org/10.3390/toxins11070392 - 4 Jul 2019

Cited by 11 | Viewed by 4014

Abstract

Antimicrobial peptides are potential molecules for the development of novel antibiotic agents. The ZorO toxin of a type I toxin–antitoxin system in Escherichia coli O157:H7 is composed of 29 amino acids and its endogenous expression inhibits E. coli growth. However, little is known about its inhibitory mechanism. In this study, we demonstrate that the ZorO localized in the inner membrane affects the plasma membrane integrity and potential when expressed in E. coli cells, which triggers the production of cytotoxic hydroxyl radicals. We further show that five internal amino acids (Ala–Leu–Leu–Arg–Leu; ALLRL) of ZorO are necessary for its toxicity. This result prompted us to address the potential of the synthetic ALLRL peptide as an antimicrobial. Exogenously-added ALLRL peptide to Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and a fungus, Candida albicans, trigger cell membrane damage and exhibit growth defect, while having no effect on Gram-negative bacterium, E. coli. The ALLRL peptide retains its activity under the physiological salt concentrations, which is in contrast to natural antimicrobial peptides. Importantly, this peptide has no toxicity against mammalian cells. Taken together, an effective and short peptide, ALLRL, would be an attractive antimicrobial to Gram-positive bacteria and C. albicans. Full article

(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)

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14 pages, 1751 KiB

Open AccessArticle

Survey of Toxin–Antitoxin Systems in Erwinia amylovora Reveals Insights into Diversity and Functional Specificity

by Teja Shidore, Quan Zeng and Lindsay R. Triplett

Toxins 2019, 11(4), 206; https://doi.org/10.3390/toxins11040206 - 6 Apr 2019

Cited by 3 | Viewed by 3793

Abstract

Toxin–antitoxin (TA) systems are diverse genetic modules with demonstrated roles in plasmid stability, stress management, biofilm formation and antibiotic persistence. However, relatively little is known about their functional significance in plant pathogens. In this study we characterize type II and IV TA systems in the economically important plant pathogen Erwinia amylovora. Hidden Markov Model (HMM) and BLAST-based programs were used to predict the identity and distribution of putative TA systems among sequenced genomes of E. amylovora and other plant-associated Erwinia spp. Of six conserved TA systems tested for function from E. amylovora, three (CbtA/CbeA, ParE/RHH and Doc/PhD) were validated as functional. CbtA was toxic to E. amylovora, but not to Escherichia coli. While the E. coli homolog of CbtA elicits the formation of lemon-shaped cells upon overexpression and targets cytoskeletal proteins FtsZ and MreB, E. amylovora CbtA led to cell elongation and did not interact with these cytoskeletal proteins. Phylogenetic analysis revealed that E. amylovora CbtA belongs to a distinct clade from the CbtA of pathogenic E. coli. This study expands the repertoire of experimentally validated TA systems in plant pathogenic bacteria, and suggests that the E. amylovora homolog of CbtA is functionally distinct from that of E. coli. Full article

(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)

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18 pages, 1643 KiB

Open AccessArticle

Pseudomonas putida Responds to the Toxin GraT by Inducing Ribosome Biogenesis Factors and Repressing TCA Cycle Enzymes

by Andres Ainelo, Rando Porosk, Kalle Kilk, Sirli Rosendahl, Jaanus Remme and Rita Hõrak

Toxins 2019, 11(2), 103; https://doi.org/10.3390/toxins11020103 - 9 Feb 2019

Cited by 6 | Viewed by 5125

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 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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17 pages, 3000 KiB

Open AccessArticle

Toxin ζ Reduces the ATP and Modulates the Uridine Diphosphate-N-acetylglucosamine Pool

by María Moreno-del Álamo, Mariangela Tabone, Juan Muñoz-Martínez, José R. Valverde and Juan C. Alonso

Toxins 2019, 11(1), 29; https://doi.org/10.3390/toxins11010029 - 9 Jan 2019

Cited by 8 | Viewed by 3221

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 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, P_i, 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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15 pages, 2656 KiB

Open AccessArticle

Identification of Three Type II Toxin-Antitoxin Systems in Streptococcus suis Serotype 2

by Jiali Xu, Nian Zhang, Manman Cao, Sujing Ren, Ting Zeng, Minglu Qin, Xigong Zhao, Fangyan Yuan, Huanchun Chen and Weicheng Bei

Toxins 2018, 10(11), 467; https://doi.org/10.3390/toxins10110467 - 13 Nov 2018

Cited by 10 | Viewed by 4404

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 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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12 pages, 3437 KiB

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

by Yueying Zhang, Bin Xia, Mei Li, Jing Shi, Yuqing Long, Yongxin Jin, Fang Bai, Zhihui Cheng, Shouguang Jin and Weihui Wu

Toxins 2018, 10(11), 424; https://doi.org/10.3390/toxins10110424 - 24 Oct 2018

Cited by 25 | Viewed by 4207

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 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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15 pages, 2001 KiB

Open AccessArticle

The Streptococcus pneumoniae yefM-yoeB and relBE Toxin-Antitoxin Operons Participate in Oxidative Stress and Biofilm Formation

by Wai Ting Chan, Mirian Domenech, Inmaculada Moreno-Córdoba, Verónica Navarro-Martínez, Concha Nieto, Miriam Moscoso, Ernesto García and Manuel Espinosa

Toxins 2018, 10(9), 378; https://doi.org/10.3390/toxins10090378 - 18 Sep 2018

Cited by 35 | Viewed by 5913

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, 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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18 pages, 7557 KiB

Open AccessArticle

Bacillus subtilis Type I antitoxin SR6 Promotes Degradation of Toxin yonT mRNA and Is Required to Prevent Toxic yoyJ Overexpression

by Celine Reif, Charlotte Löser and Sabine Brantl

Toxins 2018, 10(2), 74; https://doi.org/10.3390/toxins10020074 - 7 Feb 2018

Cited by 14 | Viewed by 5047

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 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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18 pages, 3799 KiB

Open AccessEditor’s ChoiceReview

Toxin–Antitoxin Systems in Bacillus subtilis

by Sabine Brantl and Peter Müller

Toxins 2019, 11(5), 262; https://doi.org/10.3390/toxins11050262 - 9 May 2019

Cited by 30 | Viewed by 7199

Abstract

Toxin–antitoxin (TA) systems were originally discovered as plasmid maintenance systems in a multitude of free-living bacteria, but were afterwards found to also be widespread in bacterial chromosomes. TA loci comprise two genes, one coding for a stable toxin whose overexpression kills the cell or causes growth stasis, and the other coding for an unstable antitoxin that counteracts toxin action. Of the currently known six types of TA systems, in Bacillus subtilis, so far only type I and type II TA systems were found, all encoded on the chromosome. Here, we review our present knowledge of these systems, the mechanisms of antitoxin and toxin action, and the regulation of their expression, and we discuss their evolution and possible physiological role. Full article

(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)

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16 pages, 1924 KiB

Open AccessEditor’s ChoiceReview

Type I Toxin-Antitoxin Systems in Clostridia

by Olga Soutourina

Toxins 2019, 11(5), 253; https://doi.org/10.3390/toxins11050253 - 6 May 2019

Cited by 17 | Viewed by 4313

Abstract

Type I toxin-antitoxin (TA) modules are abundant in both bacterial plasmids and chromosomes and usually encode a small hydrophobic toxic protein and an antisense RNA acting as an antitoxin. The RNA antitoxin neutralizes toxin mRNA by inhibiting its translation and/or promoting its degradation. This review summarizes our current knowledge of the type I TA modules identified in Clostridia species focusing on the recent findings in the human pathogen Clostridium difficile. More than ten functional type I TA modules have been identified in the genome of this emerging enteropathogen that could potentially contribute to its fitness and success inside the host. Despite the absence of sequence homology, the comparison of these newly identified type I TA modules with previously studied systems in other Gram-positive bacteria, i.e., Bacillus subtilis and Staphylococcus aureus, revealed some important common traits. These include the conservation of characteristic sequence features for small hydrophobic toxic proteins, the localization of several type I TA within prophage or prophage-like regions and strong connections with stress response. Potential functions in the stabilization of genome regions, adaptations to stress conditions and interactions with CRISPR-Cas defence system, as well as promising applications of TA for genome-editing and antimicrobial developments are discussed. Full article

(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)

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21 pages, 1750 KiB

Open AccessReview

A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability

by Sung-Min Kang, Do-Hee Kim, Chenglong Jin and Bong-Jin Lee

Toxins 2018, 10(12), 515; https://doi.org/10.3390/toxins10120515 - 4 Dec 2018

Cited by 46 | Viewed by 8068

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 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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