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Toxin-Antitoxin System in Bacteria

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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 (15 May 2016) | Viewed by 93408

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Toxin antitoxin (TA) systems are gaining more and more attendance as key modulators in bacterial lifestyle. Originally identified as plasmid maintenance systems, their function was considered to be exclusively to kill offspring devoid of the plasmid. More recently, TA systems were shown to be wide-spread in bacteria, and novel families of TA systems are continuously reported in the literature. These systems are not only found to be encoded on plasmids, but are also highly prevalent on the chromosomes of bacteria. A multitude of different functions have been attributed to TA systems, such as ranging from being selfish entities to systems that play major roles in bacterial persistence, biofilm formation, or virulence. Nevertheless, the current picture of TA system seems to be far from complete. Thus, there are constant discussions and sometimes revisions in the field and, as a matter of fact, conflicting hypotheses have been established in the past.

TA systems, however, are currently at a crossroad of research, and they are emerging as important factors that support bacteria, for instance, during stress conditions, in sustaining unfavorable conditions, or in pathogenicity. Important questions, such as: how are the expression and activation of TA systems regulated, what is the biological implication of their horizontal and lateral spread, why are there so many, and so forth, are still waiting to be answered for many systems? Thus, Toxins decided to launch a Special Issue on this topic to which you are invited to contribute your research.

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Toxin-Antitoxin System in Toxins (6 articles)

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3449 KiB

Open AccessArticle

Type II Toxin–Antitoxin Systems in the Unicellular Cyanobacterium Synechocystis sp. PCC 6803

by Stefan Kopfmann, Stefanie K. Roesch and Wolfgang R. Hess

Toxins 2016, 8(7), 228; https://doi.org/10.3390/toxins8070228 - 21 Jul 2016

Cited by 24 | Viewed by 7333

Abstract

Bacterial toxin–antitoxin (TA) systems are genetic elements, which are encoded by plasmid as well as chromosomal loci. They mediate plasmid and genomic island maintenance through post-segregational killing mechanisms but may also have milder effects, acting as mobile stress response systems that help certain cells of a population in persisting adverse growth conditions. Very few cyanobacterial TA system have been characterized thus far. In this work, we focus on the cyanobacterium Synechocystis 6803, a widely used model organism. We expand the number of putative Type II TA systems from 36 to 69 plus seven stand-alone components. Forty-seven TA pairs are located on the chromosome and 22 are plasmid-located. Different types of toxins are associated with various antitoxins in a mix and match principle. According to protein domains and experimental data, 81% of all toxins in Synechocystis 6803 likely exhibit RNase activity, suggesting extensive potential for toxicity-related RNA degradation and toxin-mediated transcriptome remodeling. Of particular interest is the Ssr8013–Slr8014 system encoded on plasmid pSYSG, which is part of a larger defense island or the pSYSX system Slr6056–Slr6057, which is linked to a bacterial ubiquitin-like system. Consequently, Synechocystis 6803 is one of the most prolific sources of new information about these genetic elements. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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4352 KiB

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Mapping Protein–Protein Interactions of the Resistance-Related Bacterial Zeta Toxin–Epsilon Antitoxin Complex (ε₂ζ₂) with High Affinity Peptide Ligands Using Fluorescence Polarization

by María Isabel Fernández-Bachiller, Iwona Brzozowska, Norbert Odolczyk, Urszula Zielenkiewicz, Piotr Zielenkiewicz and Jörg Rademann

Toxins 2016, 8(7), 222; https://doi.org/10.3390/toxins8070222 - 16 Jul 2016

Cited by 11 | Viewed by 6696

Abstract

Toxin–antitoxin systems constitute a native survival strategy of pathogenic bacteria and thus are potential targets of antibiotic drugs. Here, we target the Zeta–Epsilon toxin–antitoxin system, which is responsible for the stable maintenance of certain multiresistance plasmids in Gram-positive bacteria. Peptide ligands were designed on the basis of the ε₂ζ₂ complex. Three α helices of Zeta forming the protein–protein interaction (PPI) site were selected and peptides were designed conserving the residues interacting with Epsilon antitoxin while substituting residues binding intramolecularly to other parts of Zeta. Designed peptides were synthesized with an N-terminal fluoresceinyl-carboxy-residue for binding assays and provided active ligands, which were used to define the hot spots of the ε₂ζ₂ complex. Further shortening and modification of the binding peptides provided ligands with affinities <100 nM, allowing us to determine the most relevant PPIs and implement a robust competition binding assay. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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3279 KiB

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Characterization of the Deep-Sea Streptomyces sp. SCSIO 02999 Derived VapC/VapB Toxin-Antitoxin System in Escherichia coli

by Yunxue Guo, Jianyun Yao, Chenglong Sun, Zhongling Wen and Xiaoxue Wang

Toxins 2016, 8(7), 195; https://doi.org/10.3390/toxins8070195 - 01 Jul 2016

Cited by 10 | Viewed by 5775

Abstract

Toxin-antitoxin (TA) systems are small genetic elements that are ubiquitous in prokaryotes. Most studies on TA systems have focused on commensal and pathogenic bacteria; yet very few studies have focused on TAs in marine bacteria, especially those isolated from a deep sea environment. Here, we characterized a type II VapC/VapB TA system from the deep-sea derived Streptomyces sp. SCSIO 02999. The VapC (virulence-associated protein) protein belongs to the PIN (PilT N-terminal) superfamily. Overproduction of VapC strongly inhibited cell growth and resulted in a bleb-containing morphology in E. coli. The toxicity of VapC was neutralized through direct protein–protein interaction by a small protein antitoxin VapB encoded by a neighboring gene. Antitoxin VapB alone or the VapB/VapC complex negatively regulated the vapBC promoter activity. We further revealed that three conserved Asp residues in the PIN domain were essential for the toxic effect of VapC. Additionally, the VapC/VapB TA system stabilized plasmid in E. coli. Furthermore, VapC cross-activated transcription of several TA operons via a partially Lon-dependent mechanism in E. coli, and the activated toxins accumulated more preferentially than their antitoxin partners. Collectively, we identified and characterized a new deep sea TA system in the deep sea Streptomyces sp. and demonstrated that the VapC toxin in this system can cross-activate TA operons in E. coli. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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6385 KiB

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Evolution of the SpoIISABC Toxin-Antitoxin-Antitoxin System in Bacilli

by Marek Gabriško and Imrich Barák

Toxins 2016, 8(6), 180; https://doi.org/10.3390/toxins8060180 - 09 Jun 2016

Cited by 6 | Viewed by 4311

Abstract

Programmed cell death in bacteria is generally associated with two-component toxin-antitoxin systems. The SpoIISABC system, originally identified in Bacillus subtilis, consists of three components: a SpoIISA toxin and the SpoIISB and SpoIISC antitoxins. SpoIISA is a membrane-bound protein, while SpoIISB and SpoIISC are small cytosolic antitoxins, which are able to bind SpoIISA and neutralize its toxicity. In the presented bioinformatics analysis, a taxonomic distribution of the genes of the SpoIISABC system is investigated; their conserved regions and residues are identified; and their phylogenetic relationships are inferred. The SpoIISABC system is part of the core genome in members of the Bacillus genus of the Firmicutes phylum. Its presence in some non-bacillus species is likely the result of horizontal gene transfer. The SpoIISB and SpoIISC antitoxins originated by gene duplications, which occurred independently in the B. subtilis and B. cereus lineages. In the B. cereus lineage, the SpoIIS module is present in two different architectures. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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1338 KiB

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AAU-Specific RNA Cleavage Mediated by MazF Toxin Endoribonuclease Conserved in Nitrosomonas europaea

by Tatsuki Miyamoto, Akiko Yokota, Satoshi Tsuneda and Naohiro Noda

Toxins 2016, 8(6), 174; https://doi.org/10.3390/toxins8060174 - 04 Jun 2016

Cited by 12 | Viewed by 5395

Abstract

Nitrosomonas europaea carries numerous toxin-antitoxin systems. However, despite the abundant representation in its chromosome, studies have not surveyed the underlying molecular functions in detail, and their biological roles remain enigmatic. In the present study, we found that a chromosomally-encoded MazF family member, predicted at the locus NE1181, is a functional toxin endoribonuclease, and constitutes a toxin-antitoxin system, together with its cognate antitoxin, MazE. Massive parallel sequencing provided strong evidence that this toxin endoribonuclease exhibits RNA cleavage activity, primarily against the AAU triplet. This sequence-specificity was supported by the results of fluorometric assays. Our results indicate that N. europaea alters the translation profile and regulates its growth using the MazF family of endoribonuclease under certain stressful conditions. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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Identification and Characterization of the HicAB Toxin-Antitoxin System in the Opportunistic Pathogen Pseudomonas aeruginosa

by Gang Li, Mengyu Shen, Shuguang Lu, Shuai Le, Yinling Tan, Jing Wang, Xia Zhao, Wei Shen, Keke Guo, Yuhui Yang, Hongbin Zhu, Xiancai Rao, Fuquan Hu and Ming Li

Toxins 2016, 8(4), 113; https://doi.org/10.3390/toxins8040113 - 19 Apr 2016

Cited by 38 | Viewed by 7517

Abstract

Toxin-antitoxin (TA) systems are small genetic modules that are widely distributed in the genomes of bacteria and archaea and have been proposed to fulfill numerous functions. Here, we describe the identification and characterization of a type II TA system, comprising the hicAB locus in the human opportunistic pathogen Pseudomonas aeruginosa. The hicAB locus consists of genes hicA and hicB encoding a toxin and its cognate antitoxin, respectively. BLAST analysis revealed that hicAB is prevalent in approximately 36% of P. aeruginosa strains and locates in the same genomic region. RT-PCR demonstrated that hicAB forms a bicistronic operon that is cotranscribed under normal growth conditions. Overproduction of HicA inhibited the growth of Escherichia coli, and this effect could be counteracted by co-expression of HicB. The Escherichia coli kill/rescue assay showed that the effect of HicA is bacteriostatic, rather than bactericidal. Deletion of hicAB had no effect on the biofilm formation and virulence of P. aeruginosa in a mice infection model. Collectively, this study presents the first characterization of the HicAB system in the opportunistic pathogen P. aeruginosa. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

by Ki-Young Lee and Bong-Jin Lee

Toxins 2016, 8(10), 305; https://doi.org/10.3390/toxins8100305 - 22 Oct 2016

Cited by 89 | Viewed by 16425

Abstract

Bacterial toxin–antitoxin (TA) systems have received increasing attention for their diverse identities, structures, and functional implications in cell cycle arrest and survival against environmental stresses such as nutrient deficiency, antibiotic treatments, and immune system attacks. In this review, we describe the biological functions and the auto-regulatory mechanisms of six different types of TA systems, among which the type II TA system has been most extensively studied. The functions of type II toxins include mRNA/tRNA cleavage, gyrase/ribosome poison, and protein phosphorylation, which can be neutralized by their cognate antitoxins. We mainly explore the similar but divergent structures of type II TA proteins from 12 important pathogenic bacteria, including various aspects of protein–protein interactions. Accumulating knowledge about the structure–function correlation of TA systems from pathogenic bacteria has facilitated a novel strategy to develop antibiotic drugs that target specific pathogens. These molecules could increase the intrinsic activity of the toxin by artificially interfering with the intermolecular network of the TA systems. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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Structure, Evolution, and Functions of Bacterial Type III Toxin-Antitoxin Systems

by Nathalie Goeders, Ray Chai, Bihe Chen, Andrew Day and George P. C. Salmond

Toxins 2016, 8(10), 282; https://doi.org/10.3390/toxins8100282 - 28 Sep 2016

Cited by 39 | Viewed by 7235

Abstract

Toxin-antitoxin (TA) systems are small genetic modules that encode a toxin (that targets an essential cellular process) and an antitoxin that neutralises or suppresses the deleterious effect of the toxin. Based on the molecular nature of the toxin and antitoxin components, TA systems are categorised into different types. Type III TA systems, the focus of this review, are composed of a toxic endoribonuclease neutralised by a non-coding RNA antitoxin in a pseudoknotted configuration. Bioinformatic analysis shows that the Type III systems can be classified into subtypes. These TA systems were originally discovered through a phage resistance phenotype arising due to a process akin to an altruistic suicide; the phenomenon of abortive infection. Some Type III TA systems are bifunctional and can stabilise plasmids during vegetative growth and sporulation. Features particular to Type III systems are explored here, emphasising some of the characteristics of the RNA antitoxin and how these may affect the co-evolutionary relationship between toxins and cognate antitoxins in their quaternary structures. Finally, an updated analysis of the distribution and diversity of these systems are presented and discussed. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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Toxin-Antitoxin Systems in Clinical Pathogens

by Laura Fernández-García, Lucia Blasco, Maria Lopez, German Bou, Rodolfo García-Contreras, Thomas Wood and María Tomas

Toxins 2016, 8(7), 227; https://doi.org/10.3390/toxins8070227 - 20 Jul 2016

Cited by 80 | Viewed by 14040

Abstract

Toxin-antitoxin (TA) systems are prevalent in bacteria and archaea. Although not essential for normal cell growth, TA systems are implicated in multiple cellular functions associated with survival under stress conditions. Clinical strains of bacteria are currently causing major human health problems as a result of their multidrug resistance, persistence and strong pathogenicity. Here, we present a review of the TA systems described to date and their biological role in human pathogens belonging to the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) and others of clinical relevance (Escherichia coli, Burkholderia spp., Streptococcus spp. and Mycobacterium tuberculosis). Better understanding of the mechanisms of action of TA systems will enable the development of new lines of treatment for infections caused by the above-mentioned pathogens. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways

by Meenakumari Muthuramalingam, John C. White and Christina R. Bourne

Toxins 2016, 8(7), 214; https://doi.org/10.3390/toxins8070214 - 09 Jul 2016

Cited by 75 | Viewed by 7215

Abstract

Toxin-antitoxin (TA) modules are bacterial regulatory switches that facilitate conflicting outcomes for cells by promoting a pro-survival phenotypic adaptation and/or by directly mediating cell death, all through the toxin activity upon degradation of antitoxin. Intensive study has revealed specific details of TA module functions, but significant gaps remain about the molecular details of activation via antitoxin degradation used by different bacteria and in different environments. This review summarizes the current state of knowledge about the interaction of antitoxins with cellular proteases Lon and ClpP to mediate TA module activation. An understanding of these processes can answer long-standing questions regarding stochastic versus specific activation of TA modules and provide insight into the potential for manipulation of TA modules to alter bacterial growth. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications

by Chew Chieng Yeo, Fauziah Abu Bakar, Wai Ting Chan, Manuel Espinosa and Jennifer Ann Harikrishna

Toxins 2016, 8(2), 49; https://doi.org/10.3390/toxins8020049 - 19 Feb 2016

Cited by 23 | Viewed by 9705

Abstract

Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and the other, its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin, causing activation of the toxin, leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell, including acting as mediators of programmed cell death, the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications, which are the subject of this review. Here, we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes, for the containment of genetically modified organisms, and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)

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