Journal articles: 'Bacterial Toxin-antitoxin'

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Kim, Yoonji, and Jihwan Hwang. "Bacterial Toxin-antitoxin Systems and Their Biotechnological Applications." Journal of Life Science 26, no. 2 (February 25, 2016): 265–74. http://dx.doi.org/10.5352/jls.2016.26.2.265.

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Guglielmini, Julien, and Laurence Van Melderen. "Bacterial toxin-antitoxin systems." Mobile Genetic Elements 1, no. 4 (November 2011): 283–306. http://dx.doi.org/10.4161/mge.18477.

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Walling, Lauren R., and J. Scott Butler. "Structural Determinants for Antitoxin Identity and Insulation of Cross Talk between Homologous Toxin-Antitoxin Systems." Journal of Bacteriology 198, no. 24 (September 26, 2016): 3287–95. http://dx.doi.org/10.1128/jb.00529-16.

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ABSTRACT Toxin-antitoxin (TA) systems are ubiquitous in bacteria and archaea, where they play a pivotal role in the establishment and maintenance of dormancy. Under normal growth conditions, the antitoxin neutralizes the toxin. However, under conditions of stress, such as nutrient starvation or antibiotic treatment, cellular proteases degrade the antitoxin, and the toxin functions to arrest bacterial growth. We characterized the specificity determinants of the interactions between VapB antitoxins and VapC toxins from nontypeable Haemophilus influenzae (NTHi) in an effort to gain a better understanding of how antitoxins control toxin activity and bacterial persistence. We studied truncated and full-length antitoxins with single amino acid mutations in the toxin-binding domain. Coexpressing the toxin and antitoxin in Escherichia coli and measuring bacterial growth by dilution plating assayed the ability of the mutant antitoxins to neutralize the toxin. Our results identified two single amino acid residues (W48 and F52) in the C-terminal region of the VapB2 antitoxin necessary for its ability to neutralize its cognate VapC2 toxin. Additionally, we attempted to alter the specificity of VapB1 by making a mutation that would allow it to neutralize its noncognate toxin. A mutation in VapB1 to contain the tryptophan residue identified herein as important in the VapB2-VapC2 interaction resulted in a VapB1 mutant (the T47W mutant) that binds to and neutralizes both its cognate VapC1 and noncognate VapC2 toxins. This represents the first example of a single mutation causing relaxed specificity in a type II antitoxin. IMPORTANCE Toxin-antitoxin systems are of particular concern in pathogenic organisms, such as nontypeable Haemophilus influenzae , as they can elicit dormancy and persistence, leading to chronic infections and failure of antibiotic treatment. Despite the importance of the TA interaction, the specificity determinants for VapB-VapC complex formation remain uncharacterized. Thus, our understanding of how antitoxins control toxin-induced dormancy and bacterial persistence requires thorough investigation of antitoxin specificity for its cognate toxin. This study characterizes the crucial residues of the VapB2 antitoxin from NTHi necessary for its interaction with VapC2 and provides the first example of a single amino acid change altering the toxin specificity of an antitoxin.

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Piscotta, Frank J., Philip D. Jeffrey, and A. James Link. "ParST is a widespread toxin–antitoxin module that targets nucleotide metabolism." Proceedings of the National Academy of Sciences 116, no. 3 (December 31, 2018): 826–34. http://dx.doi.org/10.1073/pnas.1814633116.

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Toxin–antitoxin (TA) systems interfere with essential cellular processes and are implicated in bacterial lifestyle adaptations such as persistence and the biofilm formation. Here, we present structural, biochemical, and functional data on an uncharacterized TA system, the COG5654–COG5642 pair. Bioinformatic analysis showed that this TA pair is found in 2,942 of the 16,286 distinct bacterial species in the RefSeq database. We solved a structure of the toxin bound to a fragment of the antitoxin to 1.50 Å. This structure suggested that the toxin is a mono-ADP-ribosyltransferase (mART). The toxin specifically modifies phosphoribosyl pyrophosphate synthetase (Prs), an essential enzyme in nucleotide biosynthesis conserved in all organisms. We propose renaming the toxin ParT for Prs ADP-ribosylating toxin and ParS for the cognate antitoxin. ParT is a unique example of an intracellular protein mART in bacteria and is the smallest known mART. This work demonstrates that TA systems can induce bacteriostasis through interference with nucleotide biosynthesis.

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Nonin-Lecomte, Sylvie, Laurence Fermon, Brice Felden, and Marie-Laure Pinel-Marie. "Bacterial Type I Toxins: Folding and Membrane Interactions." Toxins 13, no. 7 (July 14, 2021): 490. http://dx.doi.org/10.3390/toxins13070490.

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Bacterial type I toxin-antitoxin systems are two-component genetic modules that encode a stable toxic protein whose ectopic overexpression can lead to growth arrest or cell death, and an unstable RNA antitoxin that inhibits toxin translation during growth. These systems are widely spread among bacterial species. Type I antitoxins are cis- or trans-encoded antisense small RNAs that interact with toxin-encoding mRNAs by pairing, thereby inhibiting toxin mRNA translation and/or inducing its degradation. Under environmental stress conditions, the up-regulation of the toxin and/or the antitoxin degradation by specific RNases promote toxin translation. Most type I toxins are small hydrophobic peptides with a predicted α-helical transmembrane domain that induces membrane depolarization and/or permeabilization followed by a decrease of intracellular ATP, leading to plasmid maintenance, growth adaptation to environmental stresses, or persister cell formation. In this review, we describe the current state of the art on the folding and the membrane interactions of these membrane-associated type I toxins from either Gram-negative or Gram-positive bacteria and establish a chronology of their toxic effects on the bacterial cell. This review also includes novel structural results obtained by NMR concerning the sprG1-encoded membrane peptides that belong to the sprG1/SprF1 type I TA system expressed in Staphylococcus aureus and discusses the putative membrane interactions allowing the lysis of competing bacteria and host cells.

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Manikandan, Parthasarathy, Sankaran Sandhya, Kavyashree Nadig, Souradip Paul, Narayanaswamy Srinivasan, Ulli Rothweiler, and Mahavir Singh. "Identification, functional characterization, assembly and structure of ToxIN type III toxin–antitoxin complex from E. coli." Nucleic Acids Research 50, no. 3 (January 8, 2022): 1687–700. http://dx.doi.org/10.1093/nar/gkab1264.

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Abstract Toxin–antitoxin (TA) systems are proposed to play crucial roles in bacterial growth under stress conditions such as phage infection. The type III TA systems consist of a protein toxin whose activity is inhibited by a noncoding RNA antitoxin. The toxin is an endoribonuclease, while the antitoxin consists of multiple repeats of RNA. The toxin assembles with the individual antitoxin repeats into a cyclic complex in which the antitoxin forms a pseudoknot structure. While structure and functions of some type III TA systems are characterized, the complex assembly process is not well understood. Using bioinformatics analysis, we have identified type III TA systems belonging to the ToxIN family across different Escherichia coli strains and found them to be clustered into at least five distinct clusters. Furthermore, we report a 2.097 Å resolution crystal structure of the first E. coli ToxIN complex that revealed the overall assembly of the protein-RNA complex. Isothermal titration calorimetry experiments showed that toxin forms a high-affinity complex with antitoxin RNA resulting from two independent (5′ and 3′ sides of RNA) RNA binding sites on the protein. These results further our understanding of the assembly of type III TA complexes in bacteria.

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Syed, Mohammad Adnan, and Céline M. Lévesque. "Chromosomal bacterial type II toxin–antitoxin systems." Canadian Journal of Microbiology 58, no. 5 (May 2012): 553–62. http://dx.doi.org/10.1139/w2012-025.

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Most prokaryotic chromosomes contain a number of toxin–antitoxin (TA) modules consisting of a pair of genes that encode 2 components, a stable toxin and its cognate labile antitoxin. TA systems are also known as addiction modules, since the cells become “addicted” to the short-lived antitoxin product (the unstable antitoxin is degraded faster than the more stable toxin) because its de novo synthesis is essential for their survival. While toxins are always proteins, antitoxins are either RNAs (type I, type III) or proteins (type II). Type II TA systems are widely distributed throughout the chromosomes of almost all free-living bacteria and archaea. The vast majority of type II toxins are mRNA-specific endonucleases arresting cell growth through the mechanism of RNA cleavage, thus preventing the translation process. The physiological role of chromosomal type II TA systems still remains the subject of debate. This review describes the currently known type II toxins and their characteristics. The different hypotheses that have been proposed to explain their role in bacterial physiology are also discussed.

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Alonso, Juan C. "Toxin–Antitoxin Systems in Pathogenic Bacteria." Toxins 13, no. 2 (January 20, 2021): 74. http://dx.doi.org/10.3390/toxins13020074.

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Toxin–antitoxin (TA) systems, which are ubiquitously present in plasmids, bacterial and archaeal genomes, are classified as types I to VI, according to the nature of the antitoxin and to the mode of toxin inhibition [...]

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Brantl, Sabine. "Bacterial type I toxin-antitoxin systems." RNA Biology 9, no. 12 (December 2012): 1488–90. http://dx.doi.org/10.4161/rna.23045.

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Díaz-Orejas, Ramón, Elizabeth Diago-Navarro, Ana María Hernández Arriaga, Juan López-Villarejo, Marc Lemonnier, Inma Moreno-Córdoba, Concha Nieto, and Manuel Espinosa. "Bacterial toxin-antitoxin systems targeting translation." Journal of Applied Biomedicine 8, no. 4 (July 31, 2010): 179–88. http://dx.doi.org/10.2478/v10136-009-0021-9.

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Gerdes, Kenn, and Etienne Maisonneuve. "Bacterial Persistence and Toxin-Antitoxin Loci." Annual Review of Microbiology 66, no. 1 (October 13, 2012): 103–23. http://dx.doi.org/10.1146/annurev-micro-092611-150159.

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Cook, Gregory M., Jennifer R. Robson, Rebekah A. Frampton, Joanna McKenzie, Rita Przybilski, Peter C. Fineran, and Vickery L. Arcus. "Ribonucleases in bacterial toxin–antitoxin systems." Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1829, no. 6-7 (June 2013): 523–31. http://dx.doi.org/10.1016/j.bbagrm.2013.02.007.

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Brantl, Sabine, and Peter Müller. "Toxin–Antitoxin Systems in Bacillus subtilis." Toxins 11, no. 5 (May 9, 2019): 262. http://dx.doi.org/10.3390/toxins11050262.

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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.

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Boss, Lidia, Marcin Górniak, Alicja Lewańczyk, Joanna Morcinek-Orłowska, Sylwia Barańska, and Agnieszka Szalewska-Pałasz. "Identification of Three Type II Toxin-Antitoxin Systems in Model Bacterial Plant Pathogen Dickeya dadantii 3937." International Journal of Molecular Sciences 22, no. 11 (May 31, 2021): 5932. http://dx.doi.org/10.3390/ijms22115932.

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Type II toxin-antitoxin (TA) systems are genetic elements usually encoding two proteins: a stable toxin and an antitoxin, which binds the toxin and neutralizes its toxic effect. The disturbance in the intracellular toxin and antitoxin ratio typically leads to inhibition of bacterial growth or bacterial cell death. Despite the fact that TA modules are widespread in bacteria and archaea, the biological role of these systems is ambiguous. Nevertheless, a number of studies suggests that the TA modules are engaged in such important processes as biofilm formation, stress response or virulence and maintenance of mobile genetic elements. The Dickeya dadantii 3937 strain serves as a model for pathogens causing the soft-rot disease in a wide range of angiosperm plants. Until now, several chromosome-encoded type II TA systems were identified in silico in the genome of this economically important bacterium, however so far only one of them was experimentally validated. In this study, we investigated three putative type II TA systems in D. dadantii 3937: ccdAB2Dda, phd-docDda and dhiTA, which represents a novel toxin/antitoxin superfamily. We provide an experimental proof for their functionality in vivo both in D. dadantii and Escherichia coli. Finally, we examined the prevalence of those systems across the Pectobacteriaceae family by a phylogenetic analysis.

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Kristoffersen, P., G. B. Jensen, K. Gerdes, and J. Piškur. "Bacterial Toxin-Antitoxin Gene System as Containment Control in Yeast Cells." Applied and Environmental Microbiology 66, no. 12 (December 1, 2000): 5524–26. http://dx.doi.org/10.1128/aem.66.12.5524-5526.2000.

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ABSTRACT The potential of a bacterial toxin-antitoxin gene system for use in containment control in eukaryotes was explored. The Escherichia coli relE and relB genes were expressed in the yeastSaccharomyces cerevisiae. Expression of therelE gene was highly toxic to yeast cells. However, expression of the relB gene counteracted the effect ofrelE to some extent, suggesting that toxin-antitoxin interaction also occurs in S. cerevisiae. Thus, bacterial toxin-antitoxin gene systems also have potential applications in the control of cell proliferation in eukaryotic cells, especially in those industrial fermentation processes in which the escape of genetically modified cells would be considered highly risky.

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Nieto, Concha, Izhack Cherny, Seok Kooi Khoo, Mario García de Lacoba, Wai Ting Chan, Chew Chieng Yeo, Ehud Gazit, and Manuel Espinosa. "The yefM-yoeB Toxin-Antitoxin Systems of Escherichia coli and Streptococcus pneumoniae: Functional and Structural Correlation." Journal of Bacteriology 189, no. 4 (October 27, 2006): 1266–78. http://dx.doi.org/10.1128/jb.01130-06.

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ABSTRACT Toxin-antitoxin loci belonging to the yefM-yoeB family are located in the chromosome or in some plasmids of several bacteria. We cloned the yefM-yoeB locus of Streptococcus pneumoniae, and these genes encode bona fide antitoxin (YefM Spn ) and toxin (YoeB Spn ) products. We showed that overproduction of YoeB Spn is toxic to Escherichia coli cells, leading to severe inhibition of cell growth and to a reduction in cell viability; this toxicity was more pronounced in an E. coli B strain than in two E. coli K-12 strains. The YoeB Spn -mediated toxicity could be reversed by the cognate antitoxin, YefM Spn , but not by overproduction of the E. coli YefM antitoxin. The pneumococcal proteins were purified and were shown to interact with each other both in vitro and in vivo. Far-UV circular dichroism analyses indicated that the pneumococcal antitoxin was partially, but not totally, unfolded and was different than its E. coli counterpart. Molecular modeling showed that the toxins belonging to the family were homologous, whereas the antitoxins appeared to be specifically designed for each bacterial locus; thus, the toxin-antitoxin interactions were adapted to the different bacterial environmental conditions. Both structural features, folding and the molecular modeled structure, could explain the lack of cross-complementation between the pneumococcal and E. coli antitoxins.

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Sat, Boaz, Ronen Hazan, Tova Fisher, Hanita Khaner, Gad Glaser, and Hanna Engelberg-Kulka. "Programmed Cell Death in Escherichia coli: Some Antibiotics Can Trigger mazEFLethality." Journal of Bacteriology 183, no. 6 (March 15, 2001): 2041–45. http://dx.doi.org/10.1128/jb.183.6.2041-2045.2001.

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ABSTRACT The discovery of toxin-antitoxin gene pairs (also called addiction modules) on extrachromosomal elements of Escherichia coli, and particularly the discovery of homologous modules on the bacterial chromosome, suggest that a potential for programmed cell death may be inherent in bacterial cultures. We have reported on the E. coli mazEF system, a regulatable addiction module located on the bacterial chromosome. MazF is a stable toxin and MazE is a labile antitoxin. Here we show that cell death mediated by the E. coli mazEF module can be triggered by several antibiotics (rifampicin, chloramphenicol, and spectinomycin) that are general inhibitors of transcription and/or translation. These antibiotics inhibit the continuous expression of the labile antitoxin MazE, and as a result, the stable toxin MazF causes cell death. Our results have implications for the possible mode(s) of action of this group of antibiotics.

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Burbank, Lindsey P., and Drake C. Stenger. "The DinJ/RelE Toxin-Antitoxin System Suppresses Bacterial Proliferation and Virulence of Xylella fastidiosa in Grapevine." Phytopathology® 107, no. 4 (April 2017): 388–94. http://dx.doi.org/10.1094/phyto-10-16-0374-r.

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Xylella fastidiosa, the causal agent of Pierce’s disease of grapes, is a slow-growing, xylem-limited, bacterial pathogen. Disease progression is characterized by systemic spread of the bacterium through xylem vessel networks, causing leaf-scorching symptoms, senescence, and vine decline. It appears to be advantageous to this pathogen to avoid excessive blockage of xylem vessels, because living bacterial cells are generally found in plant tissue with low bacterial cell density and minimal scorching symptoms. The DinJ/RelE toxin-antitoxin system is characterized here for a role in controlling bacterial proliferation and population size during plant colonization. The DinJ/RelE locus is transcribed from two separate promoters, allowing for coexpression of antitoxin DinJ with endoribonuclease toxin RelE, in addition to independent expression of RelE. The ratio of antitoxin/toxin expressed is dependent on bacterial growth conditions, with lower amounts of antitoxin present under conditions designed to mimic grapevine xylem sap. A knockout mutant of DinJ/RelE exhibits a hypervirulent phenotype, with higher bacterial populations and increased symptom development and plant decline. It is likely that DinJ/RelE acts to prevent excessive population growth, contributing to the ability of the pathogen to spread systemically without completely blocking the xylem vessels and increasing probability of acquisition by the insect vector.

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Zamakhaev, M. V., A. V. Goncharenko, and M. S. Shumkov. "Toxin-Antitoxin Systems and Bacterial Persistence (Review)." Applied Biochemistry and Microbiology 55, no. 6 (November 2019): 571–81. http://dx.doi.org/10.1134/s0003683819060140.

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Akarsu, Hatice, Patricia Bordes, Moise Mansour, Donna-Joe Bigot, Pierre Genevaux, and Laurent Falquet. "TASmania: A bacterial Toxin-Antitoxin Systems database." PLOS Computational Biology 15, no. 4 (April 25, 2019): e1006946. http://dx.doi.org/10.1371/journal.pcbi.1006946.

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Fasani, Rick A., and Michael A. Savageau. "Unrelated toxin–antitoxin systems cooperate to induce persistence." Journal of The Royal Society Interface 12, no. 108 (July 2015): 20150130. http://dx.doi.org/10.1098/rsif.2015.0130.

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Persisters are drug-tolerant bacteria that account for the majority of bacterial infections. They are not mutants, rather, they are slow-growing cells in an otherwise normally growing population. It is known that the frequency of persisters in a population is correlated with the number of toxin–antitoxin systems in the organism. Our previous work provided a mechanistic link between the two by showing how multiple toxin–antitoxin systems, which are present in nearly all bacteria, can cooperate to induce bistable toxin concentrations that result in a heterogeneous population of slow- and fast-growing cells. As such, the slow-growing persisters are a bet-hedging subpopulation maintained under normal conditions. For technical reasons, the model assumed that the kinetic parameters of the various toxin–antitoxin systems in the cell are identical, but experimental data indicate that they differ, sometimes dramatically. Thus, a critical question remains: whether toxin–antitoxin systems from the diverse families, often found together in a cell, with significantly different kinetics, can cooperate in a similar manner. Here, we characterize the interaction of toxin–antitoxin systems from many families that are unrelated and kinetically diverse, and identify the essential determinant for their cooperation. The generic architecture of toxin–antitoxin systems provides the potential for bistability, and our results show that even when they do not exhibit bistability alone, unrelated systems can be coupled by the growth rate to create a strongly bistable, hysteretic switch between normal (fast-growing) and persistent (slow-growing) states. Different combinations of kinetic parameters can produce similar toxic switching thresholds, and the proximity of the thresholds is the primary determinant of bistability. Stochastic fluctuations can spontaneously switch all of the toxin–antitoxin systems in a cell at once. The spontaneous switch creates a heterogeneous population of growing and non-growing cells, typical of persisters, that exist under normal conditions, rather than only as an induced response. The frequency of persisters in the population can be tuned for a particular environmental niche by mixing and matching unrelated systems via mutation, horizontal gene transfer and selection.

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Rathore, Jitendra Singh, and Lalit Kumar Gautam. "Expression, Purification, and Functional Analysis of Novel RelE Operon fromX. nematophila." Scientific World Journal 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/428159.

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Bacterial toxin-antitoxin (TA) complexes induce programmed cell death and also function to relieve cell from stress by various response mechanisms.Escherichia coliRelB-RelE TA complex consists of a RelE toxin functionally counteracted by RelB antitoxin. In the present study, a novel homolog of RelE toxin designated as Xn-relE toxin fromXenorhabdus nematophilapossessing its own antitoxin designated as Xn-relEAT has been identified. Expression and purification of recombinant proteins under native conditions with GST and Ni-NTA chromatography prove the existence of novel TA module. The expression of recombinant Xn-relE under tightly regulated ara promoter inE. coliTop 10 cells confirms its toxic nature in endogenous toxicity assay. The neutralization activity in endogenous toxicity assay by Xn-relEAT antitoxin confirms its antidote nature when studying the whole TA operon under ara regulated promoter. This study promotes newly discovered TA module to be regarded as important as other proteins of type II toxin-antitoxin system.

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Wilbaux, Myriam, Natacha Mine, Anne-Marie Guérout, Didier Mazel, and Laurence Van Melderen. "Functional Interactions between Coexisting Toxin-Antitoxin Systems of the ccd Family in Escherichia coli O157:H7." Journal of Bacteriology 189, no. 7 (January 26, 2007): 2712–19. http://dx.doi.org/10.1128/jb.01679-06.

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ABSTRACT Toxin-antitoxin (TA) systems are widely represented on mobile genetic elements as well as in bacterial chromosomes. TA systems encode a toxin and an antitoxin neutralizing it. We have characterized a homolog of the ccd TA system of the F plasmid (ccd F) located in the chromosomal backbone of the pathogenic O157:H7 Escherichia coli strain (ccd O157). The ccd F and the ccd O157 systems coexist in O157:H7 isolates, as these pathogenic strains contain an F-related virulence plasmid carrying the ccd F system. We have shown that the chromosomal ccd O157 system encodes functional toxin and antitoxin proteins that share properties with their plasmidic homologs: the CcdBO157 toxin targets the DNA gyrase, and the CcdAO157 antitoxin is degraded by the Lon protease. The ccd O157 chromosomal system is expressed in its natural context, although promoter activity analyses revealed that its expression is weaker than that of ccd F. ccd O157 is unable to mediate postsegregational killing when cloned in an unstable plasmid, supporting the idea that chromosomal TA systems play a role(s) other than stabilization in bacterial physiology. Our cross-interaction experiments revealed that the chromosomal toxin is neutralized by the plasmidic antitoxin while the plasmidic toxin is not neutralized by the chromosomal antitoxin, whether expressed ectopically or from its natural context. Moreover, the ccd F system is able to mediate postsegregational killing in an E. coli strain harboring the ccd O157 system in its chromosome. This shows that the plasmidic ccd F system is functional in the presence of its chromosomal counterpart.

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El Mortaji, Lamya, Alejandro Tejada-Arranz, Aline Rifflet, Ivo G. Boneca, Gérard Pehau-Arnaudet, J. Pablo Radicella, Stéphanie Marsin, and Hilde De Reuse. "A peptide of a type I toxin−antitoxin system inducesHelicobacter pylorimorphological transformation from spiral shape to coccoids." Proceedings of the National Academy of Sciences 117, no. 49 (November 23, 2020): 31398–409. http://dx.doi.org/10.1073/pnas.2016195117.

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Toxin−antitoxin systems are found in many bacterial chromosomes and plasmids with roles ranging from plasmid stabilization to biofilm formation and persistence. In these systems, the expression/activity of the toxin is counteracted by an antitoxin, which, in type I systems, is an antisense RNA. While the regulatory mechanisms of these systems are mostly well defined, the toxins’ biological activity and expression conditions are less understood. Here, these questions were investigated for a type I toxin−antitoxin system (AapA1−IsoA1) expressed from the chromosome of the human pathogenHelicobacter pylori. We show that expression of the AapA1 toxin inH. pyloricauses growth arrest associated with rapid morphological transformation from spiral-shaped bacteria to round coccoid cells. Coccoids are observed in patients and during in vitro growth as a response to different stress conditions. The AapA1 toxin, first molecular effector of coccoids to be identified, targetsH. pyloriinner membrane without disrupting it, as visualized by cryoelectron microscopy. The peptidoglycan composition of coccoids is modified with respect to spiral bacteria. No major changes in membrane potential or adenosine 5′-triphosphate (ATP) concentration result from AapA1 expression, suggesting coccoid viability. Single-cell live microscopy tracking the shape conversion suggests a possible association of this process with cell elongation/division interference. Oxidative stress induces coccoid formation and is associated with repression of the antitoxin promoter and enhanced processing of its transcript, leading to an imbalance in favor of AapA1 toxin expression. Our data support the hypothesis of viable coccoids with characteristics of dormant bacteria that might be important inH. pyloriinfections refractory to treatment.

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Tamman, Hedvig, Andres Ainelo, Mari Tagel, and Rita Hõrak. "Stability of the GraA Antitoxin Depends on Growth Phase, ATP Level, and Global Regulator MexT." Journal of Bacteriology 198, no. 5 (December 14, 2015): 787–96. http://dx.doi.org/10.1128/jb.00684-15.

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ABSTRACTBacterial type II toxin-antitoxin systems consist of a potentially poisonous toxin and an antitoxin that inactivates the toxic protein by binding to it. Most of the toxins regulate stress survival, but their activation depends on the stability of the antitoxin that has to be degraded in order for the toxin to be able to attack its cellular targets. The degradation of antitoxins is usually rapid and carried out by ATP-dependent protease Lon or Clp, which is activated under stress conditions. ThegraTAsystem ofPseudomonas putidaencodes the toxin GraT, which can affect the growth rate and stress tolerance of bacteria but is under most conditions inactivated by the unusually stable antitoxin GraA. Here, we aimed to describe the stability features of the antitoxin GraA by analyzing its degradation rate in total cell lysates ofP. putida. We show that the degradation rate of GraA depends on the growth phase of bacteria being fastest in the transition from exponential to stationary phase. In accordance with this, higher ATP levels were shown to stabilize GraA. Differently from other antitoxins, the main cellular proteases Lon and Clp are not involved in GraA stability. Instead, GraA seems to be degraded through a unique pathway involving an endoprotease that cleaves the antitoxin into two unequal parts. We also identified the global transcriptional regulator MexT as a factor for destabilization of GraA, which indicates that the degradation of GraA may be induced by conditions similar to those that activate MexT.IMPORTANCEToxin-antitoxin (TA) modules are widespread in bacterial chromosomes and have important roles in stress tolerance. As activation of a type II toxin is triggered by proteolytic degradation of the antitoxin, knowledge about the regulation of the antitoxin stability is critical for understanding the activation of a particular TA module. Here, we report on the unusual degradation pathway of the antitoxin GraA of the recently characterized GraTA system. While GraA is uncommonly stable in the exponential and late-stationary phases, its degradation increases in the transition phase. The degradation pathway of GraA involves neither Lon nor Clp, which usually targets antitoxins, but rather an unknown endoprotease and the global regulator MexT, suggesting a new type of regulation of antitoxin stability.

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Brown, Jason M., and Karen Joy Shaw. "A Novel Family of Escherichia coli Toxin-Antitoxin Gene Pairs." Journal of Bacteriology 185, no. 22 (November 15, 2003): 6600–6608. http://dx.doi.org/10.1128/jb.185.22.6600-6608.2003.

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ABSTRACT Bacterial toxin-antitoxin protein pairs (TA pairs) encode a toxin protein, which poisons cells by binding and inhibiting an essential enzyme, and an antitoxin protein, which binds the toxin and restores viability. We took an approach that did not rely on sequence homology to search for unidentified TA pairs in the genome of Escherichia coli K-12. Of 32 candidate genes tested, ectopic expression of 6 caused growth inhibition. In this report, we focus on the initial characterization of yeeV, ykfI, and ypjF, a novel family of toxin proteins. Coexpression of the gene upstream of each toxin restored the growth rate to that of the uninduced strain. Unexpectedly, we could not detect in vivo protein-protein interactions between the new toxin and antitoxin pairs. Instead, the antitoxins appeared to function by causing a large reduction in the level of cellular toxin protein.

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Huerta-Uribe, Alejandro, and Andrew J. Roe. "Disarming the enemy: targeting bacterial toxins with small molecules." Emerging Topics in Life Sciences 1, no. 1 (April 21, 2017): 31–39. http://dx.doi.org/10.1042/etls20160013.

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The rapid emergence of antibiotic-resistant bacterial strains has prompted efforts to find new and more efficacious treatment strategies. Targeting virulence factors produced by pathogenic bacteria has gained particular attention in the last few years. One of the inherent advantages of this approach is that it provides less selective pressure for the development of resistance mechanisms. In addition, antivirulence drugs could potentially be the answer for diseases in which the use of conventional antibiotics is counterproductive. That is the case for bacterial toxin-mediated diseases, in which the severity of the symptoms is a consequence of the exotoxins produced by the pathogen. Examples of these are haemolytic-uraemic syndrome produced by Shiga toxins, the profuse and dangerous dehydration caused by Cholera toxin or the life-threatening colitis occasioned by clostridial toxins. This review focuses on the recent advances on the development of small molecules with antitoxin activity against Enterohaemorrhagic Escherichia coli, Vibrio cholerae and Clostridium difficile given their epidemiological importance. The present work includes studies of small molecules with antitoxin properties that act directly on the toxin (direct inhibitors) or that act by preventing expression of the toxin (indirect inhibitors).

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Zielenkiewicz, Urszula, and Piotr Cegłowski. "The Toxin-Antitoxin System of the Streptococcal Plasmid pSM19035." Journal of Bacteriology 187, no. 17 (September 1, 2005): 6094–105. http://dx.doi.org/10.1128/jb.187.17.6094-6105.2005.

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ABSTRACT pSM19035 of the pathogenic bacterium Streptococcus pyogenes is a low-copy-number plasmid carrying erythromycin resistance, stably maintained in a broad range of gram-positive bacteria. We show here that the ω-ε-ζ operon of this plasmid constitutes a novel proteic plasmid addiction system in which the ε and ζ genes encode an antitoxin and toxin, respectively, while ω plays an autoregulatory function. Expression of toxin Zeta is bactericidal for the gram-positive Bacillus subtilis and bacteriostatic for the gram-negative Escherichia coli. The toxic effects of ζ gene expression in both bacterial species are counteracted by proper expression of ε. The ε-ζ toxin-antitoxin cassette stabilizes plasmids in E. coli less efficiently than in B. subtilis.

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Muñoz-Gómez, Ana J., Marc Lemonnier, Sandra Santos-Sierra, Alfredo Berzal-Herranz, and Ramón Díaz-Orejas. "RNase/Anti-RNase Activities of the Bacterial parD Toxin-Antitoxin System." Journal of Bacteriology 187, no. 9 (May 1, 2005): 3151–57. http://dx.doi.org/10.1128/jb.187.9.3151-3157.2005.

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ABSTRACT The bacterial parD toxin-antitoxin system of plasmid R1 encodes two proteins, the Kid toxin and its cognate antitoxin, Kis. Kid cleaves RNA and inhibits protein synthesis and cell growth in Escherichia coli. Here, we show that Kid promotes RNA degradation and inhibition of protein synthesis in rabbit reticulocyte lysates. These new activities of the Kid toxin were counteracted by the Kis antitoxin and were not displayed by the KidR85W variant, which is nontoxic in E. coli. Moreover, while Kid cleaved single- and double-stranded RNA with a preference for UAA or UAC triplets, KidR85W maintained this sequence preference but hardly cleaved double-stranded RNA. Kid was formerly shown to inhibit DNA replication of the ColE1 plasmid. Here we provide in vitro evidence that Kid cleaves the ColE1 RNA II primer, which is required for the initiation of ColE1 replication. In contrast, KidR85W did not affect the stability of RNA II, nor did it inhibit the in vitro replication of ColE1. Thus, the endoribonuclease and the cytotoxic and DNA replication-inhibitory activities of Kid seem tightly correlated. We propose that the spectrum of action of this toxin extends beyond the sole inhibition of protein synthesis to control a broad range of RNA-regulated cellular processes.

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Van Melderen, Laurence, and Manuel Saavedra De Bast. "Bacterial Toxin–Antitoxin Systems: More Than Selfish Entities?" PLoS Genetics 5, no. 3 (March 27, 2009): e1000437. http://dx.doi.org/10.1371/journal.pgen.1000437.

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Buts, Lieven, Jurij Lah, Minh-Hoa Dao-Thi, Lode Wyns, and Remy Loris. "Toxin–antitoxin modules as bacterial metabolic stress managers." Trends in Biochemical Sciences 30, no. 12 (December 2005): 672–79. http://dx.doi.org/10.1016/j.tibs.2005.10.004.

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Markovski, Monica, and Sue Wickner. "Preventing Bacterial Suicide: A Novel Toxin-Antitoxin Strategy." Molecular Cell 52, no. 5 (December 2013): 611–12. http://dx.doi.org/10.1016/j.molcel.2013.11.018.

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Równicki, Marcin, Robert Lasek, Joanna Trylska, and Dariusz Bartosik. "Targeting Type II Toxin–Antitoxin Systems as Antibacterial Strategies." Toxins 12, no. 9 (September 4, 2020): 568. http://dx.doi.org/10.3390/toxins12090568.

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The identification of novel targets for antimicrobial agents is crucial for combating infectious diseases caused by evolving bacterial pathogens. Components of bacterial toxin–antitoxin (TA) systems have been recognized as promising therapeutic targets. These widespread genetic modules are usually composed of two genes that encode a toxic protein targeting an essential cellular process and an antitoxin that counteracts the activity of the toxin. Uncontrolled toxin expression may elicit a bactericidal effect, so they may be considered “intracellular molecular bombs” that can lead to elimination of their host cells. Based on the molecular nature of antitoxins and their mode of interaction with toxins, TA systems have been classified into six groups. The most prevalent are type II TA systems. Due to their ubiquity among clinical isolates of pathogenic bacteria and the essential processes targeted, they are promising candidates for the development of novel antimicrobial strategies. In this review, we describe the distribution of type II TA systems in clinically relevant human pathogens, examine how these systems could be developed as the targets for novel antibacterials, and discuss possible undesirable effects of such therapeutic intervention, such as the induction of persister cells, biofilm formation and toxicity to eukaryotic cells.

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Saavedra De Bast, Manuel, Natacha Mine, and Laurence Van Melderen. "Chromosomal Toxin-Antitoxin Systems May Act as Antiaddiction Modules." Journal of Bacteriology 190, no. 13 (April 25, 2008): 4603–9. http://dx.doi.org/10.1128/jb.00357-08.

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ABSTRACT Toxin-antitoxin (TA) systems are widespread among bacterial chromosomes and mobile genetic elements. Although in plasmids TA systems have a clear role in their vertical inheritance by selectively killing plasmid-free daughter cells (postsegregational killing or addiction phenomenon), the physiological role of chromosomally encoded ones remains under debate. The assumption that chromosomally encoded TA systems are part of stress response networks and/or programmed cell death machinery has been called into question recently by the observation that none of the five canonical chromosomally encoded TA systems in the Escherichia coli chromosome seem to confer any selective advantage under stressful conditions (V. Tsilibaris, G. Maenhaut-Michel, N. Mine, and L. Van Melderen, J. Bacteriol. 189:6101-6108, 2007). Their prevalence in bacterial chromosomes indicates that they might have been acquired through horizontal gene transfer. Once integrated in chromosomes, they might in turn interfere with their homologues encoded by mobile genetic elements. In this work, we show that the chromosomally encoded Erwinia chrysanthemi ccd (control of cell death) (ccdEch ) system indeed protects the cell against postsegregational killing mediated by its F-plasmid ccd (ccd F) homologue. Moreover, competition experiments have shown that this system confers a fitness advantage under postsegregational conditions mediated by the ccd F system. We propose that ccdEch acts as an antiaddiction module and, more generally, that the integration of TA systems in bacterial chromosomes could drive the evolution of plasmid-encoded ones and select toxins that are no longer recognized by the antiaddiction module.

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Li, Ming, Luyao Gong, Feiyue Cheng, Haiying Yu, Dahe Zhao, Rui Wang, Tian Wang, et al. "Toxin-antitoxin RNA pairs safeguard CRISPR-Cas systems." Science 372, no. 6541 (April 29, 2021): eabe5601. http://dx.doi.org/10.1126/science.abe5601.

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CRISPR-Cas systems provide RNA-guided adaptive immunity in prokaryotes. We report that the multisubunit CRISPR effector Cascade transcriptionally regulates a toxin-antitoxin RNA pair, CreTA. CreT (Cascade-repressed toxin) is a bacteriostatic RNA that sequesters the rare arginine tRNAUCU (transfer RNA with anticodon UCU). CreA is a CRISPR RNA–resembling antitoxin RNA, which requires Cas6 for maturation. The partial complementarity between CreA and the creT promoter directs Cascade to repress toxin transcription. Thus, CreA becomes antitoxic only in the presence of Cascade. In CreTA-deleted cells, cascade genes become susceptible to disruption by transposable elements. We uncover several CreTA analogs associated with diverse archaeal and bacterial CRISPR-cas loci. Thus, toxin-antitoxin RNA pairs can safeguard CRISPR immunity by making cells addicted to CRISPR-Cas, which highlights the multifunctionality of Cas proteins and the intricate mechanisms of CRISPR-Cas regulation.

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Yoshizumi, Satoshi, Yonglong Zhang, Yoshihiro Yamaguchi, Liang Chen, Barry N. Kreiswirth, and Masayori Inouye. "Staphylococcus aureus YoeB Homologues Inhibit Translation Initiation." Journal of Bacteriology 191, no. 18 (July 6, 2009): 5868–72. http://dx.doi.org/10.1128/jb.00623-09.

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ABSTRACT YoeB is a bacterial toxin encoded by the yefM-yoeB toxin-antitoxin system found in various bacterial genomes. Here, we show that Staphylococcus aureus contains two YoeB homologues, both of which function as ribosome-dependent mRNA interferases to inhibit translation initiation in a manner identical to that of YoeB-ec from Escherichia coli.

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Soutourina, Olga. "Type I Toxin-Antitoxin Systems in Clostridia." Toxins 11, no. 5 (May 6, 2019): 253. http://dx.doi.org/10.3390/toxins11050253.

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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.

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Lee, Min Woo, Elizabeth E. Rogers, and Drake C. Stenger. "Xylella fastidiosa Plasmid-Encoded PemK Toxin Is an Endoribonuclease." Phytopathology® 102, no. 1 (January 2012): 32–40. http://dx.doi.org/10.1094/phyto-05-11-0150.

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Stable inheritance of pXF-RIV11 in Xylella fastidiosa is conferred by the pemI/pemK toxin-antitoxin (TA) system. PemK toxin inhibits bacterial growth; PemI is the corresponding antitoxin that blocks activity of PemK by direct binding. PemK and PemI were overexpressed in Escherichia coli and activities of each were assessed. Purified PemK toxin specifically degraded single-stranded RNA but not double-stranded RNA, double-stranded DNA, or single-stranded DNA. Addition of PemI antitoxin inhibited nuclease activity of PemK toxin. Purified complexes of PemI bound to PemK exhibited minimal nuclease activity; removal of PemI antitoxin from the complex restored nuclease activity of PemK toxin. Sequencing of 5′ rapid amplification of cDNA ends products of RNA targets digested with PemK revealed a preference for cleavage between U and A residues of the sequence UACU and UACG. Nine single amino-acid substitution mutants of PemK toxin were constructed and evaluated for growth inhibition, ribonuclease activity, and PemI binding. Three PemK point-substitution mutants (R3A, G16E, and D79V) that lacked nuclease activity did not inhibit growth. All nine PemK mutants retained the ability to bind PemI. Collectively, the results indicate that the mechanism of stable inheritance conferred by pXF-RIV11 pemI/pemK is similar to that of the R100 pemI/pemK TA system of E. coli.

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Beck, Izaak N., Ben Usher, Hannah G. Hampton, Peter C. Fineran, and Tim R. Blower. "Antitoxin autoregulation of M. tuberculosis toxin-antitoxin expression through negative cooperativity arising from multiple inverted repeat sequences." Biochemical Journal 477, no. 12 (June 26, 2020): 2401–19. http://dx.doi.org/10.1042/bcj20200368.

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Toxin-antitoxin systems play key roles in bacterial adaptation, including protection from antibiotic assault and infection by bacteriophages. The type IV toxin-antitoxin system AbiE encodes a DUF1814 nucleotidyltransferase-like toxin, and a two-domain antitoxin. In Streptococcus agalactiae, the antitoxin AbiEi negatively autoregulates abiE expression through positively co-operative binding to inverted repeats within the promoter. The human pathogen Mycobacterium tuberculosis encodes four DUF1814 putative toxins, two of which have antitoxins homologous to AbiEi. One such M. tuberculosis antitoxin, named Rv2827c, is required for growth and whilst the structure has previously been solved, the mode of regulation is unknown. To complete the gaps in our understanding, we first solved the structure of S. agalactiae AbiEi to 1.83 Å resolution for comparison with M. tuberculosis Rv2827c. AbiEi contains an N-terminal DNA binding domain and C-terminal antitoxicity domain, with bilateral faces of opposing charge. The overall AbiEi fold is similar to Rv2827c, though smaller, and with a 65° difference in C-terminal domain orientation. We further demonstrate that, like AbiEi, Rv2827c can autoregulate toxin-antitoxin operon expression. In contrast with AbiEi, the Prv2827c promoter contains two sets of inverted repeats, which bind Rv2827c with differing affinities depending on the sequence consensus. Surprisingly, Rv2827c bound with negative co-operativity to the full Prv2827c promoter, demonstrating an unexpectedly complex form of transcriptional regulation.

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Ichige, Asao, and Ichizo Kobayashi. "Stability of EcoRI Restriction-Modification Enzymes In Vivo Differentiates the EcoRI Restriction-Modification System from Other Postsegregational Cell Killing Systems." Journal of Bacteriology 187, no. 19 (October 1, 2005): 6612–21. http://dx.doi.org/10.1128/jb.187.19.6612-6621.2005.

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ABSTRACT Certain type II restriction modification gene systems can kill host cells when these gene systems are eliminated from the host cells. Such ability to cause postsegregational killing of host cells is the feature of bacterial addiction modules, each of which consists of toxin and antitoxin genes. With these addiction modules, the differential stability of toxin and antitoxin molecules in cells plays an essential role in the execution of postsegregational killing. We here examined in vivo stability of the EcoRI restriction enzyme (toxin) and modification enzyme (antitoxin), the gene system of which has previously been shown to cause postsegregational host killing in Escherichia coli. Using two different methods, namely, quantitative Western blot analysis and pulse-chase immunoprecipitation analysis, we demonstrated that both the EcoRI restriction enzyme and modification enzyme are as stable as bulk cellular proteins and that there is no marked difference in their stability. The numbers of EcoRI restriction and modification enzyme molecules present in a host cell during the steady-state growth were estimated. We monitored changes in cellular levels of the EcoRI restriction and modification enzymes during the postsegregational killing. Results from these analyses together suggest that the EcoRI gene system does not rely on differential stability between the toxin and the antitoxin molecules for execution of postsegregational cell killing. Our results provide insights into the mechanism of postsegregational killing by restriction-modification systems, which seems to be distinct from mechanisms of postsegregational killing by other bacterial addiction modules.

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Kędzierska, Barbara, and Finbarr Hayes. "Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis." Molecules 21, no. 6 (June 17, 2016): 790. http://dx.doi.org/10.3390/molecules21060790.

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Page, Rebecca, and Wolfgang Peti. "Toxin-antitoxin systems in bacterial growth arrest and persistence." Nature Chemical Biology 12, no. 4 (March 18, 2016): 208–14. http://dx.doi.org/10.1038/nchembio.2044.

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Wu, Jie, Aihua Deng, Qinyun Sun, Hua Bai, Zhaopeng Sun, Xiuling Shang, Yun Zhang, et al. "Bacterial Genome Editing via a Designed Toxin–Antitoxin Cassette." ACS Synthetic Biology 7, no. 3 (January 17, 2017): 822–31. http://dx.doi.org/10.1021/acssynbio.6b00287.

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Verdon, Gregory, Lauren DeStefano, Chi Wang, Gregory Boel, Guy Montelione, Nancy Woychik, and John F. Hunt. "Structural and Functional Studies of Bacterial Toxin-Antitoxin Systems." Biophysical Journal 98, no. 3 (January 2010): 246a—247a. http://dx.doi.org/10.1016/j.bpj.2009.12.1341.

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Tu, Chih-Han, Michelle Holt, Shengfeng Ruan, and Christina Bourne. "Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems." Toxins 12, no. 6 (June 26, 2020): 422. http://dx.doi.org/10.3390/toxins12060422.

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The diversity of Type-II toxin–antitoxin (TA) systems in bacterial genomes requires tightly controlled interaction specificity to ensure protection of the cell, and potentially to limit cross-talk between toxin–antitoxin pairs of the same family of TA systems. Further, there is a redundant use of toxin folds for different cellular targets and complexation with different classes of antitoxins, increasing the apparent requirement for the insulation of interactions. The presence of Type II TA systems has remained enigmatic with respect to potential benefits imparted to the host cells. In some cases, they play clear roles in survival associated with unfavorable growth conditions. More generally, they can also serve as a “cure” against acquisition of highly similar TA systems such as those found on plasmids or invading genetic elements that frequently carry virulence and resistance genes. The latter model is predicated on the ability of these highly specific cognate antitoxin–toxin interactions to form cross-reactions between chromosomal antitoxins and invading toxins. This review summarizes advances in the Type II TA system models with an emphasis on antitoxin cross-reactivity, including with invading genetic elements and cases where toxin proteins share a common fold yet interact with different families of antitoxins.

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Rankin, Daniel J., Leighton A. Turner, Jack A. Heinemann, and Sam P. Brown. "The coevolution of toxin and antitoxin genes drives the dynamics of bacterial addiction complexes and intragenomic conflict." Proceedings of the Royal Society B: Biological Sciences 279, no. 1743 (July 11, 2012): 3706–15. http://dx.doi.org/10.1098/rspb.2012.0942.

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Bacterial genomes commonly contain ‘addiction’ gene complexes that code for both a toxin and a corresponding antitoxin. As long as both genes are expressed, cells carrying the complex can remain healthy. However, loss of the complex (including segregational loss in daughter cells) can entail death of the cell. We develop a theoretical model to explore a number of evolutionary puzzles posed by toxin–antitoxin (TA) population biology. We first extend earlier results demonstrating that TA complexes can spread on plasmids, as an adaptation to plasmid competition in spatially structured environments, and highlight the role of kin selection. We then considered the emergence of TA complexes on plasmids from previously unlinked toxin and antitoxin genes. We find that one of these traits must offer at least initially a direct advantage in some but not all environments encountered by the evolving plasmid population. Finally, our study predicts non-transitive ‘rock-paper-scissors’ dynamics to be a feature of intragenomic conflict mediated by TA complexes. Intragenomic conflict could be sufficient to select deleterious genes on chromosomes and helps to explain the previously perplexing observation that many TA genes are found on bacterial chromosomes.

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Donegan, Niles P., Earl T. Thompson, Zhibiao Fu, and Ambrose L. Cheung. "Proteolytic Regulation of Toxin-Antitoxin Systems by ClpPC in Staphylococcus aureus." Journal of Bacteriology 192, no. 5 (December 28, 2009): 1416–22. http://dx.doi.org/10.1128/jb.00233-09.

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ABSTRACT Bacterial toxin-antitoxin (TA) systems typically consist of a small, labile antitoxin that inactivates a specific longer-lived toxin. In Escherichia coli, such antitoxins are proteolytically regulated by the ATP-dependent proteases Lon and ClpP. Under normal conditions, antitoxin synthesis is sufficient to replace this loss from proteolysis, and the bacterium remains protected from the toxin. However, if TA production is interrupted, antitoxin levels decrease, and the cognate toxin is free to inhibit the specific cellular component, such as mRNA, DnaB, or gyrase. To date, antitoxin degradation has been studied only in E. coli, so it remains unclear whether similar mechanisms of regulation exist in other organisms. To address this, we followed antitoxin levels over time for the three known TA systems of the major human pathogen Staphylococcus aureus, mazEF, axe1-txe1, and axe2-txe2. We observed that the antitoxins of these systems, MazE sa , Axe1, and Axe2, respectively, were all degraded rapidly (half-life [t 1/2], ∼18 min) at rates notably higher than those of their E. coli counterparts, such as MazE (t 1/2, ∼30 to 60 min). Furthermore, when S. aureus strains deficient for various proteolytic systems were examined for changes in the half-lives of these antitoxins, only strains with clpC or clpP deletions showed increased stability of the molecules. From these studies, we concluded that ClpPC serves as the functional unit for the degradation of all known antitoxins in S. aureus.

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Sala, Ambre Julie, Patricia Bordes, Sara Ayala, Nawel Slama, Samuel Tranier, Michèle Coddeville, Anne-Marie Cirinesi, Marie-Pierre Castanié-Cornet, Lionel Mourey, and Pierre Genevaux. "Directed evolution of SecB chaperones toward toxin-antitoxin systems." Proceedings of the National Academy of Sciences 114, no. 47 (November 7, 2017): 12584–89. http://dx.doi.org/10.1073/pnas.1710456114.

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SecB chaperones assist protein export in bacteria. However, certain SecB family members have diverged to become specialized toward the control of toxin-antitoxin (TA) systems known to promote bacterial adaptation to stress and persistence. In such tripartite TA-chaperone (TAC) systems, the chaperone was shown to assist folding and to prevent degradation of its cognate antitoxin, thus facilitating inhibition of the toxin. Here, we used both the export chaperone SecB ofEscherichia coliand the tripartite TAC system ofMycobacterium tuberculosisas a model to investigate how generic chaperones can specialize toward the control of TA systems. Through directed evolution of SecB, we have identified and characterized mutations that specifically improve the ability of SecB to control our model TA system without affecting its function in protein export. Such a remarkable plasticity of SecB chaperone function suggests that its substrate binding surface can be readily remodeled to accommodate specific clients.

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Pathak, Chinar, Hookang Im, Sun-bok Jang, Yeon-Jin Yang, Hye-Jin Yoon, Hong-Man Kim, Ae-Ran Kwon, and Bong-Jin Lee. "Toxins from TA system of Helicobacter pylori and insight into mRNase activity." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C828. http://dx.doi.org/10.1107/s2053273314091712.

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The toxin-antitoxin (TA) systems widely spread among bacteria and archaea are important for antibiotic resistance and virulence. The bacterial kingdom uses TA systems to adjust the global level of gene expression and translation through RNA degradation. The HP0892-HP0893 and HP0894-HP0895 toxin-antitoxin systems are the only two known TA systems belonging to Helicobacter pylori. In both of these TA systems, the antitoxin binds and inhibits the toxin and regulates the transcription of the TA operon. However, the precise molecular basis for interaction with substrate or antitoxin and the mechanism of mRNA cleavage remains unclear. Therefore, here an attempt was made to shed some light on the mechanism behind the TA system of HP0892-HP0893 and HP0894-HP0895. Here, we present the crystal structures of apo- and copper-bound HP0894 at 1.28 Å and 1.89 Å, respectively, and the crystal structure of the zinc-bound HP0892 toxin at 1.8 Å resolution. Reorientation of residues involving the mRNase active site was shown. Through the combined approach of structural analysis along with isothermal calorimetry studies and structural homology search, the amino acids involved in mRNase active site were monitored. In the mRNase active site of HP0894 toxin, His84 acts as a catalytic residue and reorients itself acting as a general acid in an acid-base catalysis reaction, while His47 and His60 stabilize the transition state. Glu58 acts as a general base, and substrate reorientation is caused by Phe88. In the mRNase active site of HP0892 toxin, the most catalytically important residue, His86, reorients itself to exhibit RNase activity while Glu58 acts as a general base. His47 and His60 are considered to be involved in enzymatic activity. Glu58 and Asp64 are involved in substrate binding and specific sequence recognition. The mutational constructs were used for isothermal calorimetric studies to analyze the effect of catalytic residues.

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Goulard, Céline, Sophie Langrand, Elisabeth Carniel, and Sylvie Chauvaux. "The Yersinia pestis Chromosome Encodes Active Addiction Toxins." Journal of Bacteriology 192, no. 14 (May 14, 2010): 3669–77. http://dx.doi.org/10.1128/jb.00336-10.

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ABSTRACT Toxin-antitoxin (TA) loci consist of two genes in an operon, encoding a stable toxin and an unstable antitoxin. The expression of toxin leads to cell growth arrest and sometimes bacterial death, while the antitoxin prevents the cytotoxic activity of the toxin. In this study, we show that the chromosome of Yersinia pestis, the causative agent of plague, carries 10 putative TA modules and two solitary antitoxins that belong to five different TA families (HigBA, HicAB, RelEB, Phd/Doc, and MqsRA). Two of these toxin genes (higB2 and hicA1) could not be cloned in Escherichia coli unless they were coexpressed with their cognate antitoxin gene, indicating that they are highly toxic for this species. One of these toxin genes (higB2) could, however, be cloned directly and expressed in Y. pestis, where it was highly toxic, while the other one (hicA1) could not, probably because of its extreme toxicity. All eight other toxin genes were successfully cloned into the expression vector pBAD-TOPO. For five of them (higB1, higB3, higB5, hicA2, and tox), no toxic activity was detected in either E. coli or Y. pestis despite their overexpression. The three remaining toxin genes (relE1, higB4, and doc) were toxic for E. coli, and this toxic activity was abolished when the cognate antitoxin was coexpressed, showing that these three TA modules are functional in E. coli. Curiously, only one of these three toxins (RelE1) was active in Y. pestis. Cross-interaction between modules of the same family was observed but occurred only when the antitoxins were almost identical. Therefore, our study demonstrates that of the 10 predicted TA modules encoded by the Y. pestis chromosome, at least 5 are functional in E. coli and/or in Y. pestis. This is the first demonstration of active addiction toxins produced by the plague agent.

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Journal articles on the topic 'Bacterial Toxin-antitoxin'

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