-
Advanced Biosystems Mar 2020Periodically, a scientific field should examine its early premises. For ubiquitous toxin/antitoxin (TA) systems, several initial paradigms require adjustment based on... (Review)
Review
Periodically, a scientific field should examine its early premises. For ubiquitous toxin/antitoxin (TA) systems, several initial paradigms require adjustment based on accumulated data. For example, it is now clear that under physiological conditions, there is little evidence that toxins of TA systems cause cell death and little evidence that TA systems cause persistence. Instead, TA systems are utilized to reduce metabolism during stress, inhibit phages, stabilize genetic elements, and influence biofilm formation (bacterial cells attached via an extracellular matrix). In this essay, it is argued that toxins bound to antitoxins are not likely to become activated by preferential antitoxin degradation but instead, de novo toxin synthesis in the absence of stoichiometric amounts of antitoxin activates toxins.
Topics: Antitoxins; Bacterial Physiological Phenomena; Bacterial Toxins; Toxin-Antitoxin Systems
PubMed: 32293143
DOI: 10.1002/adbi.201900290 -
Current Genetics May 2016Toxin-antitoxin (TA) modules regulate metabolism and viability of bacteria and archaea. In type II TA systems these functions are generally thought to be performed by... (Review)
Review
Toxin-antitoxin (TA) modules regulate metabolism and viability of bacteria and archaea. In type II TA systems these functions are generally thought to be performed by two small proteins. However, evidence is increasing that the toxins are much more diverse and can form multi-domain proteins. Recently, we published a novel type II TA system in which toxin and antitoxin are covalently linked into a single polypeptide chain. In this review we summarize the current knowledge on these elongated toxin homologs and provide perspectives for future study.
Topics: Animals; Antitoxins; Toxins, Biological
PubMed: 26597447
DOI: 10.1007/s00294-015-0541-7 -
Trends in Biochemical Sciences Dec 2005Bacterial genomes frequently contain operons that encode a toxin and its antidote. These 'toxin-antitoxin (TA) modules' have an important role in bacterial stress... (Review)
Review
Bacterial genomes frequently contain operons that encode a toxin and its antidote. These 'toxin-antitoxin (TA) modules' have an important role in bacterial stress physiology and might form the basis of multidrug resistance. The toxins in TA modules act as gyrase poisons or stall the ribosome by mediating the cleavage of mRNA. The antidotes contain an N-terminal DNA-binding region of variable fold and a C-terminal toxin-inhibiting domain. When bound to toxin, the C-terminal domain adopts an extended conformation. In the absence of toxin, by contrast, this domain (and sometimes the whole antidote protein) remains unstructured, allowing its fast degradation by proteolysis. Under silent conditions the antidote inhibits the toxin and the toxin-antidote complex acts as a repressor for the TA operon, whereas under conditions of activation proteolytic degradation of the antidote outpaces its synthesis.
Topics: Antitoxins; Bacteria; Bacterial Toxins; Base Sequence; DNA Gyrase; DNA, Bacterial; Evolution, Molecular; Models, Biological; Models, Molecular; Multiprotein Complexes; Protein Folding; RNA, Bacterial; RNA, Messenger
PubMed: 16257530
DOI: 10.1016/j.tibs.2005.10.004 -
Microbiology Spectrum Dec 2022Toxin-antitoxin (TA) systems are ubiquitous genetic elements in prokaryotes, but their biological importance is poorly understood. Mycobacterium smegmatis contains eight...
Toxin-antitoxin (TA) systems are ubiquitous genetic elements in prokaryotes, but their biological importance is poorly understood. Mycobacterium smegmatis contains eight putative TA systems. Previously, seven TAs have been studied, with five of them being verified as functional. Here, we show that Ms0251-0252 is a novel TA system in that expression of the toxin Ms0251 leads to growth inhibition that can be rescued by the antitoxin Ms0252. To investigate the functional roles of TA systems in M. smegmatis, we deleted the eight putative TA loci and assayed the mutants for resistance to various stresses. Deletion of all eight TA loci resulted in decreased survival under starvation conditions and altered fitness when exposed to environmental stresses. Furthermore, we showed that deletion of the eight TA loci decreased resistance to phage infection in Sauton medium compared with the results using 7H10 medium, suggesting that TA systems might have different contributions depending on the nutrient environment. Furthermore, we found that MazEF specifically played a dominant role in resistance to phage infection. Finally, transcriptome analysis revealed that MazEF overexpression led to differential expression of multiple genes, including those related to iron acquisition. Altogether, we demonstrate that TA systems coordinately function to allow M. smegmatis to adapt to changing environmental conditions. Toxin-antitoxin (TA) systems are mechanisms for rapid adaptation of bacteria to environmental changes. Mycobacterium smegmatis, a model bacterium for studying Mycobacterium tuberculosis, encodes eight putative TA systems. Here, we constructed an M. smegmatis mutant with deletions of all eight TA-encoding genes and evaluated the resistance of these mutants to environmental stresses. Our results showed that different TA systems have overlapping and, in some cases, opposing functions in adaptation to various stresses. We suggest that complementary TA modules may function together to regulate the bacterial stress response, enabling adaptation to changing environments. Together, this study provides key insights into the roles of TA systems in resistance to various environmental stresses, drug tolerance, and defense against phage infection.
Topics: Mycobacterium smegmatis; Toxin-Antitoxin Systems; Bacterial Toxins; Mycobacterium tuberculosis; Antitoxins; Bacterial Proteins
PubMed: 36318013
DOI: 10.1128/spectrum.02815-22 -
Biochimie Feb 2024Toxin-antitoxin systems (TAs) are generally two-component genetic modules present in almost every prokaryotic genome. The production of the free and active toxin is able... (Review)
Review
Toxin-antitoxin systems (TAs) are generally two-component genetic modules present in almost every prokaryotic genome. The production of the free and active toxin is able to disrupt key cellular processes leading to the growth inhibition or death of its host organism in absence of its cognate antitoxin. The functions attributed to TAs rely on this lethal phenotype ranging from mobile genetic elements stabilization to phage defense. Their abundance in prokaryotic genomes as well as their lethal potential make them attractive targets for new antibacterial strategies. The hijacking of TAs requires a deep understanding of their regulation to be able to design such approach. In this review, we summarize the accumulated knowledge on how bacteria cope with these toxic genes in their genome. The characterized TAs can be grouped based on the way they prevent toxicity. Some systems rely on a tight control of the expression to prevent the production of the toxin while others control the activity of the toxin at the post-translational level.
Topics: Toxin-Antitoxin Systems; Toxins, Biological; Bacteria; Antitoxins; Prokaryotic Cells; Bacterial Proteins
PubMed: 37473832
DOI: 10.1016/j.biochi.2023.07.013 -
Molecules (Basel, Switzerland) Jun 2016Toxin-antitoxin (TA) cassettes are encoded widely by bacteria. The modules typically comprise a protein toxin and protein or RNA antitoxin that sequesters the toxin... (Review)
Review
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.
Topics: Anti-Bacterial Agents; Antitoxins; Bacteria; Biofilms; Humans; Toxins, Biological; Virulence
PubMed: 27322231
DOI: 10.3390/molecules21060790 -
PLoS Genetics Mar 2009Bacterial toxin-antitoxin (TA) systems are diverse and widespread in the prokaryotic kingdom. They are composed of closely linked genes encoding a stable toxin that can... (Review)
Review
Bacterial toxin-antitoxin (TA) systems are diverse and widespread in the prokaryotic kingdom. They are composed of closely linked genes encoding a stable toxin that can harm the host cell and its cognate labile antitoxin, which protects the host from the toxin's deleterious effect. TA systems are thought to invade bacterial genomes through horizontal gene transfer. Some TA systems might behave as selfish elements and favour their own maintenance at the expense of their host. As a consequence, they may contribute to the maintenance of plasmids or genomic islands, such as super-integrons, by post-segregational killing of the cell that loses these genes and so suffers the stable toxin's destructive effect. The function of the chromosomally encoded TA systems is less clear and still open to debate. This Review discusses current hypotheses regarding the biological roles of these evolutionarily successful small operons. We consider the various selective forces that could drive the maintenance of TA systems in bacterial genomes.
Topics: Antitoxins; Bacterial Toxins; Escherichia coli Proteins; Genome, Bacterial; Operon; Selection, Genetic
PubMed: 19325885
DOI: 10.1371/journal.pgen.1000437 -
Microbiology and Molecular Biology... Dec 2012Pneumococcal infections cause up to 2 million deaths annually and raise a large economic burden and thus constitute an important threat to mankind. Because of the... (Review)
Review
Pneumococcal infections cause up to 2 million deaths annually and raise a large economic burden and thus constitute an important threat to mankind. Because of the increase in the antibiotic resistance of Streptococcus pneumoniae clinical isolates, there is an urgent need to find new antimicrobial approaches to triumph over pneumococcal infections. Toxin-antitoxin (TA) systems (TAS), which are present in most living bacteria but not in eukaryotes, have been proposed as an effective strategy to combat bacterial infections. Type II TAS comprise a stable toxin and a labile antitoxin that form an innocuous TA complex under normal conditions. Under stress conditions, TA synthesis will be triggered, resulting in the degradation of the labile antitoxin and the release of the toxin protein, which would poison the host cells. The three functional chromosomal TAS from S. pneumoniae that have been studied as well as their molecular characteristics are discussed in detail in this review. Furthermore, a meticulous bioinformatics search has been performed for 48 pneumococcal genomes that are found in public databases, and more putative TAS, homologous to well-characterized ones, have been revealed. Strikingly, several unusual putative TAS, in terms of components and genetic organizations previously not envisaged, have been discovered and are further discussed. Previously, we reported a novel finding in which a unique pneumococcal DNA signature, the BOX element, affected the regulation of the pneumococcal yefM-yoeB TAS. This BOX element has also been found in some of the other pneumococcal TAS. In this review, we also discuss possible relationships between some of the pneumococcal TAS with pathogenicity, competence, biofilm formation, persistence, and an interesting phenomenon called bistability.
Topics: Antitoxins; Bacterial Proteins; Bacterial Toxins; Humans; Pneumococcal Infections; Streptococcus pneumoniae
PubMed: 23204366
DOI: 10.1128/MMBR.00030-12 -
Acta Biochimica Polonica 2011Bacteria have developed multiple complex mechanisms ensuring an adequate response to environmental changes. In this context, bacterial cell division and growth are... (Review)
Review
Bacteria have developed multiple complex mechanisms ensuring an adequate response to environmental changes. In this context, bacterial cell division and growth are subject to strict control to ensure metabolic balance and cell survival. A plethora of studies cast light on toxin-antitoxin (TA) systems as metabolism regulators acting in response to environmental stress conditions. Many of those studies suggest direct relations between the TA systems and the pathogenic potential or antibiotic resistance of relevant bacteria. Other studies point out that TA systems play a significant role in ensuring stability of mobile genetic material. The evolutionary origin and relations between various TA systems are still a subject of a debate. The impact of toxin-antitoxin systems on bacteria physiology prompted their application in molecular biology as tools allowing cloning of some hard-to-maintain genes, plasmid maintenance and production of recombinant proteins.
Topics: Antitoxins; Bacterial Physiological Phenomena; Drug Resistance, Bacterial; Molecular Biology; Toxins, Biological
PubMed: 21394325
DOI: No ID Found -
Current Genetics Feb 2017Toxin-antitoxin (TA) loci were first described as killing systems for plasmid maintenance. The surprisingly abundant presence of TA loci in bacterial chromosomes has... (Review)
Review
Toxin-antitoxin (TA) loci were first described as killing systems for plasmid maintenance. The surprisingly abundant presence of TA loci in bacterial chromosomes has stimulated an extensive research in the recent decade aimed to understand the biological importance of these potentially deadly systems. Accumulating evidence suggests that the evolutionary success of genomic TA systems could be explained by their ability to increase bacterial fitness under stress conditions. While TA systems remain quiescent under favorable growth conditions, the toxins can be activated in response to stress resulting in growth suppression and development of stress-tolerant dormant state. Yet, several studies suggest that the TA-mediated stress protection is costly and traded off against decreased fitness under normal growth conditions. Here, we give an overview of the fitness benefits of the chromosomal TA systems, and discuss the costs of TA-mediated stress protection.
Topics: Adaptation, Biological; Antitoxins; Bacterial Physiological Phenomena; Bacterial Toxins; Environment; Gene Expression Regulation, Bacterial; Genetic Fitness; Microbial Viability; Stress, Physiological
PubMed: 27276988
DOI: 10.1007/s00294-016-0622-2