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Nature Reviews. Microbiology Jun 2022Toxin-antitoxin systems are widespread in bacterial genomes. They are usually composed of two elements: a toxin that inhibits an essential cellular process and an... (Review)
Review
Toxin-antitoxin systems are widespread in bacterial genomes. They are usually composed of two elements: a toxin that inhibits an essential cellular process and an antitoxin that counteracts its cognate toxin. In the past decade, a number of new toxin-antitoxin systems have been described, bringing new growth inhibition mechanisms to light as well as novel modes of antitoxicity. However, recent advances in the field profoundly questioned the role of these systems in bacterial physiology, stress response and antimicrobial persistence. This shifted the paradigm of the functions of toxin-antitoxin systems to roles related to interactions between hosts and their mobile genetic elements, such as viral defence or plasmid stability. In this Review, we summarize the recent progress in understanding the biology and evolution of these small genetic elements, and discuss how genomic conflicts could shape the diversification of toxin-antitoxin systems.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Genome, Bacterial; Genomics; Toxin-Antitoxin Systems
PubMed: 34975154
DOI: 10.1038/s41579-021-00661-1 -
Annual Review of Microbiology Sep 2022Toxin-antitoxin (TA) systems are ubiquitous genetic elements in bacteria that consist of a growth-inhibiting toxin and its cognate antitoxin. These systems are prevalent... (Review)
Review
Toxin-antitoxin (TA) systems are ubiquitous genetic elements in bacteria that consist of a growth-inhibiting toxin and its cognate antitoxin. These systems are prevalent in bacterial chromosomes, plasmids, and phage genomes, but individual systems are not highly conserved, even among closely related strains. The biological functions of TA systems have been controversial and enigmatic, although a handful of these systems have been shown to defend bacteria against their viral predators, bacteriophages. Additionally, their patterns of conservation-ubiquitous, but rapidly acquired and lost from genomes-as well as the co-occurrence of some TA systems with known phage defense elements are suggestive of a broader role in mediating phage defense. Here, we review the existing evidence for phage defense mediated by TA systems, highlighting how toxins are activated by phage infection and how toxins disrupt phage replication. We also discuss phage-encoded systems that counteract TA systems, underscoring the ongoing coevolutionary battle between bacteria and phage. We anticipate that TA systems will continue to emerge as central players in the innate immunity of bacteria against phage.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Bacteriophages; Plasmids; Toxin-Antitoxin Systems
PubMed: 35395167
DOI: 10.1146/annurev-micro-020722-013730 -
Nature Reviews. Microbiology May 2022Clostridioides difficile is a Gram-positive anaerobe that can cause a spectrum of disorders that range in severity from mild diarrhoea to fulminant colitis and/or death.... (Review)
Review
Clostridioides difficile is a Gram-positive anaerobe that can cause a spectrum of disorders that range in severity from mild diarrhoea to fulminant colitis and/or death. The bacterium produces up to three toxins, which are considered the major virulence factors in C. difficile infection. These toxins promote inflammation, tissue damage and diarrhoea. In this Review, we highlight recent biochemical and structural advances in our understanding of the mechanisms that govern host-toxin interactions. Understanding how C. difficile toxins affect the host forms a foundation for developing novel strategies for treatment and prevention of C. difficile infection.
Topics: Antitoxins; Bacterial Proteins; Bacterial Toxins; Clostridioides difficile; Diarrhea; Humans
PubMed: 34837014
DOI: 10.1038/s41579-021-00660-2 -
Microbiological Research Nov 2022Toxin-antitoxin (TA) systems, composed of a stable toxin and a cognate unstable antitoxin, are ubiquitous in the genomes of bacteria and archaea. Under suitable growth... (Review)
Review
Toxin-antitoxin (TA) systems, composed of a stable toxin and a cognate unstable antitoxin, are ubiquitous in the genomes of bacteria and archaea. Under suitable growth conditions, an antitoxin prevents its cognate toxin from inducing toxicity; nonetheless, under stress or plasmid loss, it is either rapidly degraded or downregulated, thereby freeing the toxin to exert its activity toward various targets. Currently, TA systems are classified into eight types based on the nature and mode of action of antitoxins. TA expression is tightly regulated at multiple levels. These systems have various biological roles, including genetic element maintenance, virulence, stress resistance, and phage inhibition. Because of the toxic property of toxins, TA systems have been exploited for biotechnological (e.g., DNA cloning, plasmid maintenance, and counterselection) and medical (e.g., antibacterial drugs, antivirals, and anticancer therapies) applications. Herein, we provided an updated overview of TA systems by focusing on their classification, biological roles, and applications. We also described recent advances in research on TA systems and discussed research perspectives in this field.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Plasmids; Toxin-Antitoxin Systems
PubMed: 35969944
DOI: 10.1016/j.micres.2022.127159 -
The Indian Journal of Tuberculosis Apr 2023Toxin-Antitoxin (TA) system is abundant in the microbial genome, especially in bacteria and archaea. Its genetic elements and addiction modules with the role of... (Review)
Review
Toxin-Antitoxin (TA) system is abundant in the microbial genome, especially in bacteria and archaea. Its genetic elements and addiction modules with the role of bacterial persistence and virulence. The TA system consists of a toxin and most unstable antitoxin that could be a protein or non-encoded RNA, TA loci are chromosomally determined and their cellular functions are mostly unknown. Approximately 93 TA systems were demonstrated and more functionally available in M. tuberculosis (Mtb), the organism responsible for tuberculosis (TB). It is an airborne disease, which is causing ill-health to humans. M. tuberculosis possesses higher TA loci than other microbes and non-tubercle bacilli, the following TA types have been identified such as VapBC, MazEF, HigBA, RelBE, ParDE, DarTG, PemIK, MbcTA, and one tripartite type II TAC-Chaperone system. Toxin-antitoxin Database (TADB) brings a detailed update on Toxin-Antitoxin classification in the different pathogens such as staphylococcus aureus, streptococcus pneumonia, Vibrio cholerae, Salmonella typhimurium, Shigella flexneri, and helicobacter pylori, etc. So, this Toxin-Antitoxin system is a master regulator for bacterial growth, and an essential factor in analyzing the properties and function of disease persistence, biofilm formation, and pathogenicity. The TA system is an advanced tool to develop a new therapeutic agent against M. tuberculosis.
Topics: Humans; Mycobacterium tuberculosis; Toxin-Antitoxin Systems; Bacterial Toxins; Tuberculosis; Antitoxins; Bacterial Proteins
PubMed: 37100570
DOI: 10.1016/j.ijtb.2022.05.010 -
Trends in Microbiology May 2021Toxin/antitoxin (TA) systems are present in nearly all bacterial and archaeal strains and consist of a toxin that reduces growth and an antitoxin that masks toxin... (Review)
Review
Toxin/antitoxin (TA) systems are present in nearly all bacterial and archaeal strains and consist of a toxin that reduces growth and an antitoxin that masks toxin activity. Currently there are six primary classes for TA systems based on the nature of the antitoxin and the way that the antitoxin inactivates the toxin. Here we show that there now are at least three additional and distinct TA systems in which the antitoxin is an enzyme and the cognate toxin is the direct target of the antitoxin: Hha/TomB (antitoxin oxidizes Cys18 of the toxin), TglT/TakA (antitoxin phosphorylates Ser78 of the toxin), and HepT/MntA (antitoxin adds three AMPs to Tyr104 of the toxin). Thus, we suggest the type VII TA system should be used to designate those TA systems in which the enzyme antitoxin chemically modifies the toxin post-translationally to neutralize it. Defining the type VII TA system using this specific criterion will aid researchers in classifying newly discovered TA systems as well as refine the framework for recognizing the diverse biochemical functions in TA systems.
Topics: Antitoxins; Bacteria; Bacterial Toxins; Computational Biology; Immunologic Factors; Toxin-Antitoxin Systems
PubMed: 33342606
DOI: 10.1016/j.tim.2020.12.001 -
Journal of Bacteriology Mar 2020Type II toxin-antitoxin (TA) systems are small genetic elements composed of a toxic protein and its cognate antitoxin protein, the latter counteracting the toxicity of... (Review)
Review
Type II toxin-antitoxin (TA) systems are small genetic elements composed of a toxic protein and its cognate antitoxin protein, the latter counteracting the toxicity of the former. While TA systems were initially discovered on plasmids, functioning as addiction modules through a phenomenon called postsegregational killing, they were later shown to be massively present in bacterial chromosomes, often in association with mobile genetic elements. Extensive research has been conducted in recent decades to better understand the physiological roles of these chromosomally encoded modules and to characterize the conditions leading to their activation. The diversity of their proposed roles, ranging from genomic stabilization and abortive phage infection to stress modulation and antibiotic persistence, in conjunction with the poor understanding of TA system regulation, resulted in the generation of simplistic models, often refuted by contradictory results. This review provides an epistemological and critical retrospective on TA modules and highlights fundamental questions concerning their roles and regulations that still remain unanswered.
Topics: Antitoxins; Bacterial Toxins; Biological Evolution; Genetic Association Studies; Genome, Bacterial; Phenotype; Toxin-Antitoxin Systems
PubMed: 31932311
DOI: 10.1128/JB.00763-19 -
Nature Reviews. Microbiology Sep 2022
Topics: Antitoxins; Bacterial Proteins; Bacteriophages
PubMed: 35761056
DOI: 10.1038/s41579-022-00766-1 -
Toxins Jun 2023Toxin-antitoxin (TA) systems are widely present in bacterial genomes. They consist of stable toxins and unstable antitoxins that are classified into distinct groups... (Review)
Review
Toxin-antitoxin (TA) systems are widely present in bacterial genomes. They consist of stable toxins and unstable antitoxins that are classified into distinct groups based on their structure and biological activity. TA systems are mostly related to mobile genetic elements and can be easily acquired through horizontal gene transfer. The ubiquity of different homologous and non-homologous TA systems within a single bacterial genome raises questions about their potential cross-interactions. Unspecific cross-talk between toxins and antitoxins of non-cognate modules may unbalance the ratio of the interacting partners and cause an increase in the free toxin level, which can be deleterious to the cell. Moreover, TA systems can be involved in broadly understood molecular networks as transcriptional regulators of other genes' expression or modulators of cellular mRNA stability. In nature, multiple copies of highly similar or identical TA systems are rather infrequent and probably represent a transition stage during evolution to complete insulation or decay of one of them. Nevertheless, several types of cross-interactions have been described in the literature to date. This implies a question of the possibility and consequences of the TA system cross-interactions, especially in the context of the practical application of the TA-based biotechnological and medical strategies, in which such TAs will be used outside their natural context, will be artificially introduced and induced in the new hosts. Thus, in this review, we discuss the prospective challenges of system cross-talks in the safety and effectiveness of TA system usage.
Topics: Bacterial Toxins; Prospective Studies; Toxin-Antitoxin Systems; Bacteria; Antitoxins; Biotechnology; Bacterial Proteins
PubMed: 37368681
DOI: 10.3390/toxins15060380 -
Toxins Jan 2014Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are... (Review)
Review
Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are widely spread in bacterial and archaeal genomes. TA systems have been assigned many functions, ranging from persistence to DNA stabilization or protection against mobile genetic elements. They are classified in five types, depending on the nature and mode of action of the antitoxin. In type I and III, antitoxins are RNAs that either inhibit the synthesis of the toxin or sequester it. In type II, IV and V, antitoxins are proteins that either sequester, counterbalance toxin activity or inhibit toxin synthesis. In addition to these interactions between the antitoxin and toxin components (RNA-RNA, protein-protein, RNA-protein), TA systems interact with a variety of cellular factors, e.g., toxins target essential cellular components, antitoxins are degraded by RNAses or ATP-dependent proteases. Hence, TA systems have the capacity to interact with each other at different levels. In this review, we will discuss the different interactions in which TA systems are involved and their implications in TA system functions and evolution.
Topics: Antitoxins; Bacterial Proteins; DNA, Bacterial; Escherichia coli; Protein Interaction Domains and Motifs; Toxins, Biological; Transcriptional Activation
PubMed: 24434905
DOI: 10.3390/toxins6010304