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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 May 2023"Recognizing a surprising fact is the first step towards discovery." This famous quote from Louis Pasteur is particularly appropriate to describe what led us to study... (Review)
Review
"Recognizing a surprising fact is the first step towards discovery." This famous quote from Louis Pasteur is particularly appropriate to describe what led us to study mycolactone, a lipid toxin produced by the human pathogen . is the causative agent of Buruli ulcer, a neglected tropical disease manifesting as chronic, necrotic skin lesions with a "surprising" lack of inflammation and pain. Decades after its first description, mycolactone has become much more than a mycobacterial toxin. This uniquely potent inhibitor of the mammalian translocon (Sec61) helped reveal the central importance of Sec61 activity for immune cell functions, the spread of viral particles and, unexpectedly, the viability of certain cancer cells. We report in this review the main discoveries that marked our research into mycolactone, and the medical perspectives they opened up. The story of mycolactone is not over and the applications of Sec61 inhibition may go well beyond immunomodulation, viral infections, and oncology.
Topics: Animals; Humans; Buruli Ulcer; Mycobacterium ulcerans; Macrolides; Bacterial Toxins; Mammals
PubMed: 37368670
DOI: 10.3390/toxins15060369 -
Current Genetics Feb 2019Autoregulation is the direct modulation of gene expression by the product of the corresponding gene. Autoregulation of bacterial gene expression has been mostly studied... (Review)
Review
Autoregulation is the direct modulation of gene expression by the product of the corresponding gene. Autoregulation of bacterial gene expression has been mostly studied at the transcriptional level, when a protein acts as the cognate transcriptional repressor. A recent study investigating dynamics of the bacterial toxin-antitoxin MazEF system has shown how autoregulation at both the transcriptional and post-transcriptional levels affects the heterogeneity of Escherichia coli populations. Toxin-antitoxin systems hold a crucial but still elusive part in bacterial response to stress. This perspective highlights how these modules can also serve as a great model system for investigating basic concepts in gene regulation. However, as the genomic background and environmental conditions substantially influence toxin activation, it is important to study (auto)regulation of toxin-antitoxin systems in well-defined setups as well as in conditions that resemble the environmental niche.
Topics: Bacteria; Bacterial Proteins; Bacterial Toxins; DNA-Binding Proteins; Endoribonucleases; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Homeostasis; Toxin-Antitoxin Systems
PubMed: 30132188
DOI: 10.1007/s00294-018-0879-8 -
Vaccine Jun 1985A rebirth of interest and activity in vaccine development has occurred in recent years which is probably due to the persistence of threat to health by infectious... (Review)
Review
A rebirth of interest and activity in vaccine development has occurred in recent years which is probably due to the persistence of threat to health by infectious diseases, as well as technological advances which have made possible new approaches to solve old problems. Most work being done today with vaccine development against diseases caused entirely or in part by bacterial toxins falls into the categories of, attenuated organisms (whether by classical means or application of newly developed genetic technologies), and/or toxin subunits (derived by genetic manipulations, peptide synthesis, or chemical modification of toxins). This review discusses some of these new approaches in general as well as specific examples of their application to several bacterial diseases whose pathologies involve toxins.
Topics: Animals; Bacillus anthracis; Bacteria; Bacterial Proteins; Bacterial Toxins; Bacterial Vaccines; Cholera Toxin; Diphtheria Toxin; Enterotoxins; Escherichia coli Proteins; Humans; Pseudomonas; Virulence Factors, Bordetella
PubMed: 3929492
DOI: 10.1016/0264-410x(85)90056-8 -
Toxins Apr 2018Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the genomic island, was... (Review)
Review
Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the genomic island, was discovered in 2006. Despite many efforts, colibactin has not yet been purified, and its structure remains elusive. Interestingly, the island is found in members of the family (mainly and ) isolated from different origins, including from intestinal microbiota, septicaemia, newborn meningitis, and urinary tract infections. Colibactin-producing bacteria induce chromosomal instability and DNA damage in eukaryotic cells, which leads to senescence of epithelial cells and apoptosis of immune cells. The island is mainly observed in B2 phylogroup strains, which include extra-intestinal pathogenic strains, and are over-represented in biopsies isolated from colorectal cancer. In addition, bacteria increase the number of tumours in diverse colorectal cancer mouse models. Thus, colibactin could have a major impact on human health. In the present review, we will focus on the biological effects of colibactin, the distribution of the island, and summarize what is currently known about its synthesis and its structure.
Topics: Animals; Bacterial Toxins; Genomic Islands; Humans; Mutagens; Peptides; Polyketides
PubMed: 29642622
DOI: 10.3390/toxins10040151 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Sep 2022Bacteria are often infected by large numbers of phages, and host bacteria have evolved diverse molecular strategies in the race with phages, with abortive infection... (Review)
Review
Bacteria are often infected by large numbers of phages, and host bacteria have evolved diverse molecular strategies in the race with phages, with abortive infection (Abi) being one of them. The toxin-antitoxin system (TA) is expressed in response to bacterial stress, mediating hypometabolism and even dormancy, as well as directly reducing the formation of offspring phages. In addition, some of the toxins' sequences and structures are highly homologous to Cas, and phages even encode antitoxin analogs to block the activity of the corresponding toxins. This suggests that the failure of phage infection due to bacterial death in abortive infections is highly compatible with TA function, whereas TA may be one of the main resistance and defense forces for phage infestation of the host. This review summarized the TA systems involved in phage abortive infections based on classification and function. Moreover, TA systems with abortive functions and future use in antibiotic development and disease treatment were predicted. This will facilitate the understanding of bacterial-phage interactions as well as phage therapy and related synthetic biology research.
Topics: Anti-Bacterial Agents; Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Bacteriophages; Toxin-Antitoxin Systems
PubMed: 36151800
DOI: 10.13345/j.cjb.220140 -
Biochimica Et Biophysica Acta Feb 2010Clostridial glucosylating cytotoxins, including Clostridium difficile toxins A and B, Clostridium novyi alpha-toxin, and Clostridium sordellii lethal toxin, are major... (Review)
Review
Clostridial glucosylating cytotoxins, including Clostridium difficile toxins A and B, Clostridium novyi alpha-toxin, and Clostridium sordellii lethal toxin, are major virulence factors and causative agents of human diseases. These toxins mono-O-glucosylate (or mono-O-GlcNAcylate) a specific threonine residue of Rho/Ras-proteins, which is essential for the function of the molecular switches. Recently, a related group of glucosyltransferases from Legionella pneumophila has been identified. These Legionella glucosyltransferases modify the large GTPase elongation factor eEF1A at a serine residue by mono-O-glucosylation, thereby inhibiting protein synthesis of target cells. Recent results on structures, functions and biological roles of both groups of bacterial toxin glucosyltransferases will be discussed.
Topics: Amino Acid Sequence; Bacterial Toxins; Glycosyltransferases; Humans; Legionella pneumophila; Molecular Sequence Data; Peptide Elongation Factor 1; Protein Conformation; Protein Structure, Tertiary; Sequence Alignment; Substrate Specificity; Transcription Factors; Virulence Factors; ras Proteins
PubMed: 19647041
DOI: 10.1016/j.bbagen.2009.07.022 -
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 -
Nature Mar 2022Colibactin is a chemically unstable small-molecule genotoxin that is produced by several different bacteria, including members of the human gut microbiome. Although the...
Colibactin is a chemically unstable small-molecule genotoxin that is produced by several different bacteria, including members of the human gut microbiome. Although the biological activity of colibactin has been extensively investigated in mammalian systems, little is known about its effects on other microorganisms. Here we show that colibactin targets bacteria that contain prophages, and induces lytic development through the bacterial SOS response. DNA, added exogenously, protects bacteria from colibactin, as does expressing a colibactin resistance protein (ClbS) in non-colibactin-producing cells. The prophage-inducing effects that we observe apply broadly across different phage-bacteria systems and in complex communities. Finally, we identify bacteria that have colibactin resistance genes but lack colibactin biosynthetic genes. Many of these bacteria are infected with predicted prophages, and we show that the expression of their ClbS homologues provides immunity from colibactin-triggered induction. Our study reveals a mechanism by which colibactin production could affect microbiomes and highlights a role for microbial natural products in influencing population-level events such as phage outbreaks.
Topics: Bacteria; Bacterial Toxins; Bacteriolysis; Microbial Interactions; Peptides; Polyketides; Prophages; SOS Response, Genetics; Virus Activation
PubMed: 35197633
DOI: 10.1038/s41586-022-04444-3 -
MBio Feb 2021Bacterial cells utilize toxin-antitoxin systems to inhibit self-reproduction, while maintaining viability, when faced with environmental challenges. The activation of...
Bacterial cells utilize toxin-antitoxin systems to inhibit self-reproduction, while maintaining viability, when faced with environmental challenges. The activation of the toxin is often coupled to the induction of cellular response pathways, such as the stringent response, in response to multiple stress conditions. Under these conditions, the cell enters a quiescent state referred to as dormancy or persistence. How toxin activation triggers persistence and induces a systemic stress response in the alphaproteobacteria remains unclear. Here, we report that in , a -encoded bacterial toxin contributes to bacterial persistence by manipulating intracellular amino acid balance. HipA2 is a serine/threonine kinase that deactivates tryptophanyl-tRNA synthetase by phosphorylation, leading to stalled protein synthesis and the accumulation of free tryptophan. An increased level of tryptophan allosterically activates the adenylyltransferase activity of GlnE that, in turn, deactivates glutamine synthetase GlnA by adenylylation. The inactivation of GlnA promotes the deprivation of glutamine in the cell, which triggers a stringent response. By screening 69 stress conditions, we find that HipBA2 responds to multiple stress signals through the proteolysis of HipB2 antitoxin by the Lon protease and the release of active HipA2 kinase, revealing a molecular mechanism that allows disparate stress conditions to be sensed and funneled into a single response pathway. To overcome various environmental challenges, bacterial cells can enter a physiologically quiescent state, known as dormancy or persistence, which balances growth and viability. In this study, we report a new mechanism by which a toxin-antitoxin system responds to harsh environmental conditions or nutrient deprivation by orchestrating a dormant state while preserving viability. The -encoded kinase functions as a toxin in , inducing bacterial persistence by disturbing the intracellular tryptophan-glutamine balance. A nitrogen regulatory circuit can be regulated by the intracellular level of tryptophan, which mimics the allosteric role of glutamine in this feedback loop. The HipBA2 module senses different types of stress conditions by increasing the intracellular level of tryptophan, which in turn breaks the tryptophan-glutamine balance and induces glutamine deprivation. Our results reveal a molecular mechanism that allows disparate environmental challenges to converge on a common pathway that results in a dormant state.
Topics: Amino Acids; Bacterial Proteins; Bacterial Toxins; Caulobacter; Cytoplasm; Gene Expression Regulation, Bacterial; Glutamine; Protein Biosynthesis; Toxin-Antitoxin Systems; Tryptophan
PubMed: 33622732
DOI: 10.1128/mBio.03020-20