Special Issue "Toxin-Antitoxin Systems in Pathogenic Bacteria"

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (31 July 2020).

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A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Juan Carlos Alonso
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Guest Editor
Department of Microbial Biotechnology, Centro Nacional de Biotecnología, CNB-CSIC, 28049 Madrid, Spain
Interests: homologous recombination; DNA repair; horizontal gene transfer; plasmid and chromosomal segregation; plasmid partition; toxin-antitoxins on cell physiology

Special Issue Information

Dear Colleagues,

Bacterial toxin–antitoxin (TA) systems, which are ubiquitously present in bacterial genomes, are not essential for normal cell proliferation. The TAs regulate fundamental cellular processes, facilitate survival under stress conditions, have essential roles in persistence and virulence, and represent potential therapeutic targets. These genetic TA loci are also shown to be involved in the maintenance of successful multidrug-resistant mobile genetic elements. TA systems encode a labile antitoxin and its stable toxin; degradation of the antitoxin renders a free toxin, which is bacteriostatic by nature. A free toxin generates a reversible state with low metabolic activity (quiescence) by affecting important functions of bacterial cells such as transcription, translation, DNA replication, replication and cell–wall synthesis, biofilm formation, phage predation, the regulation of nucleotide pool, etc., whereas antitoxins are toxin inhibitors. Under stress conditions, the TA systems might form networks. Understanding the basis of the unique response of TAs to stress, the prime causes for the emergence of drug-resistant strains, and their contribution to therapy failure and development of chronic and recurrent infections are necessary to grasp how TAs contribute to the mechanisms of phenotypic heterogeneity and pathogenesis that will enable the development of rational development of new treatment for infections caused by pathogens.

Prof. Dr. Juan Carlos Alonso
Guest Editor

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Keywords

  • stable toxin
  • labile antitoxin
  • bacteriostatic TA mechanism
  • bacterial persistence
  • multidrug-resistant hospital infections
  • antibacterial strategy

Published Papers (10 papers)

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Editorial

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Editorial
Toxin–Antitoxin Systems in Pathogenic Bacteria
Toxins 2021, 13(2), 74; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020074 - 20 Jan 2021
Viewed by 513
Abstract
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 [...] Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)

Research

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Article
Antitoxin ε Reverses Toxin ζ-Facilitated Ampicillin Dormants
Toxins 2020, 12(12), 801; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120801 - 15 Dec 2020
Cited by 2 | Viewed by 773
Abstract
Toxin-antitoxin (TA) modules are ubiquitous in bacteria, but their biological importance in stress adaptation remains a matter of debate. The inactive ζ-ε2-ζ TA complex is composed of one labile ε2 antitoxin dimer flanked by two stable ζ toxin monomers. Free [...] Read more.
Toxin-antitoxin (TA) modules are ubiquitous in bacteria, but their biological importance in stress adaptation remains a matter of debate. The inactive ζ-ε2-ζ TA complex is composed of one labile ε2 antitoxin dimer flanked by two stable ζ toxin monomers. Free toxin ζ reduces the ATP and GTP levels, increases the (p)ppGpp and c-di-AMP pool, inactivates a fraction of uridine diphosphate-N-acetylglucosamine, and induces reversible dormancy. A small subpopulation, however, survives toxin action. Here, employing a genetic orthogonal control of ζ and ε levels, the fate of bacteriophage SPP1 infection was analyzed. Toxin ζ induces an active slow-growth state that halts SPP1 amplification, but it re-starts after antitoxin expression rather than promoting abortive infection. Toxin ζ-induced and toxin-facilitated ampicillin (Amp) dormants have been revisited. Transient toxin ζ expression causes a metabolic heterogeneity that induces toxin and Amp dormancy over a long window of time rather than cell persistence. Antitoxin ε expression, by reversing ζ activities, facilitates the exit of Amp-induced dormancy both in rec+ and recA cells. Our findings argue that an unexploited target to fight against antibiotic persistence is to disrupt toxin-antitoxin interactions. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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Article
The Toxin-Antitoxin Systems of the Opportunistic Pathogen Stenotrophomonas maltophilia of Environmental and Clinical Origin
Toxins 2020, 12(10), 635; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12100635 - 01 Oct 2020
Cited by 1 | Viewed by 881
Abstract
Stenotrophomonas maltophilia is a ubiquitous environmental bacterium that has recently emerged as a multidrug-resistant opportunistic pathogen causing bloodstream, respiratory, and urinary tract infections. The connection between the commensal environmental S. maltophilia and the opportunistic pathogen strains is still under investigation. Bacterial toxin–antitoxin (TA) [...] Read more.
Stenotrophomonas maltophilia is a ubiquitous environmental bacterium that has recently emerged as a multidrug-resistant opportunistic pathogen causing bloodstream, respiratory, and urinary tract infections. The connection between the commensal environmental S. maltophilia and the opportunistic pathogen strains is still under investigation. Bacterial toxin–antitoxin (TA) systems have been previously associated with pathogenic traits, such as biofilm formation and resistance to antibiotics, which are important in clinical settings. The same species of the bacterium can possess various sets of TAs, possibly influencing their overall stress response. While the TA systems of other important opportunistic pathogens have been researched, nothing is known about the TA systems of S. maltophilia. Here, we report the identification and characterization of S. maltophilia type II TA systems and their prevalence in the isolates of clinical and environmental origins. We found 49 putative TA systems by bioinformatic analysis in S. maltophilia genomes. Despite their even spread in sequenced S. maltophilia genomes, we observed that relBE, hicAB, and previously undescribed COG3832-ArsR operons were present solely in clinical S. maltophilia isolates collected in Lithuania, while hipBA was more frequent in the environmental ones. The kill-rescue experiments in Escherichia coli proved higBA, hicAB, and relBE systems to be functional TA modules. Together with different TA profiles, the clinical S. maltophilia isolates exhibited stronger biofilm formation, increased antibiotic, and serum resistance compared to environmental isolates. Such tendencies suggest that certain TA systems could be used as indicators of virulence traits. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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Article
Mechanisms of Tolerance and Resistance to Chlorhexidine in Clinical Strains of Klebsiella pneumoniae Producers of Carbapenemase: Role of New Type II Toxin-Antitoxin System, PemIK
Toxins 2020, 12(9), 566; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12090566 - 02 Sep 2020
Cited by 3 | Viewed by 1522
Abstract
Although the failure of antibiotic treatment is normally attributed to resistance, tolerance and persistence display a significant role in the lack of response to antibiotics. Due to the fact that several nosocomial pathogens show a high level of tolerance and/or resistance to chlorhexidine, [...] Read more.
Although the failure of antibiotic treatment is normally attributed to resistance, tolerance and persistence display a significant role in the lack of response to antibiotics. Due to the fact that several nosocomial pathogens show a high level of tolerance and/or resistance to chlorhexidine, in this study we analyzed the molecular mechanisms associated with chlorhexidine adaptation in two clinical strains of Klebsiella pneumoniae by phenotypic and transcriptomic studies. These two strains belong to ST258-KPC3 (high-risk clone carrying β-lactamase KPC3) and ST846-OXA48 (low-risk clone carrying β-lactamase OXA48). Our results showed that the K. pneumoniae ST258-KPC3CA and ST846-OXA48CA strains exhibited a different behavior under chlorhexidine (CHLX) pressure, adapting to this biocide through resistance and tolerance mechanisms, respectively. Furthermore, the appearance of cross-resistance to colistin was observed in the ST846-OXA48CA strain (tolerant to CHLX), using the broth microdilution method. Interestingly, this ST846-OXA48CA isolate contained a plasmid that encodes a novel type II toxin/antitoxin (TA) system, PemI/PemK. We characterized this PemI/PemK TA system by cloning both genes into the IPTG-inducible pCA24N plasmid, and found their role in persistence and biofilm formation. Accordingly, the ST846-OXA48CA strain showed a persistence biphasic curve in the presence of a chlorhexidine-imipenem combination, and these results were confirmed by the enzymatic assay (WST-1). Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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Article
Molecular and Structural Basis of Cross-Reactivity in M. tuberculosis Toxin–Antitoxin Systems
Toxins 2020, 12(8), 481; https://doi.org/10.3390/toxins12080481 - 29 Jul 2020
Cited by 2 | Viewed by 1011
Abstract
Mycobacterium tuberculosis genome encodes over 80 toxin–antitoxin (TA) systems. While each toxin interacts with its cognate antitoxin, the abundance of TA systems presents an opportunity for potential non-cognate interactions. TA systems mediate manifold interactions to manage pathogenicity and stress response network of the [...] Read more.
Mycobacterium tuberculosis genome encodes over 80 toxin–antitoxin (TA) systems. While each toxin interacts with its cognate antitoxin, the abundance of TA systems presents an opportunity for potential non-cognate interactions. TA systems mediate manifold interactions to manage pathogenicity and stress response network of the cell and non-cognate interactions may play vital roles as well. To address if non-cognate and heterologous interactions are feasible and to understand the structural basis of their interactions, we have performed comprehensive computational analyses on the available 3D structures and generated structural models of paralogous M. tuberculosis VapBC and MazEF TA systems. For a majority of the TA systems, we show that non-cognate toxin–antitoxin interactions are structurally incompatible except for complexes like VapBC15 and VapBC11, which show similar interfaces and potential for cross-reactivity. For TA systems which have been experimentally shown earlier to disfavor non-cognate interactions, we demonstrate that they are structurally and stereo-chemically incompatible. For selected TA systems, our detailed structural analysis identifies specificity conferring residues. Thus, our work improves the current understanding of TA interfaces and generates a hypothesis based on congenial binding site, geometric complementarity, and chemical nature of interfaces. Overall, our work offers a structure-based explanation for non-cognate toxin-antitoxin interactions in M. tuberculosis. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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Article
mRNA Interferase Bacillus cereus BC0266 Shows MazF-Like Characteristics Through Structural and Functional Study
Toxins 2020, 12(6), 380; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12060380 - 08 Jun 2020
Cited by 2 | Viewed by 856
Abstract
Toxin–antitoxin (TA) systems are prevalent in bacteria and are known to regulate cellular growth in response to stress. As various functions related to TA systems have been revealed, the importance of TA systems are rapidly emerging. Here, we present the crystal structure of [...] Read more.
Toxin–antitoxin (TA) systems are prevalent in bacteria and are known to regulate cellular growth in response to stress. As various functions related to TA systems have been revealed, the importance of TA systems are rapidly emerging. Here, we present the crystal structure of putative mRNA interferase BC0266 and report it as a type II toxin MazF. The MazF toxin is a ribonuclease activated upon and during stressful conditions, in which it cleaves mRNA in a sequence-specific, ribosome-independent manner. Its prolonged activity causes toxic consequences to the bacteria which, in turn, may lead to bacterial death. In this study, we conducted structural and functional investigations of Bacillus cereus MazF and present the first toxin structure in the TA system of B. cereus. Specifically, B. cereus MazF adopts a PemK-like fold and also has an RNA substrate-recognizing loop, which is clearly observed in the high-resolution structure. Key residues of B. cereus MazF involved in the catalytic activity are also proposed, and in vitro assay together with mutational studies affirm the ribonucleic activity and the active sites essential for its cellular toxicity. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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Article
Multi-Stress Induction of the Mycobacterium tuberculosis MbcTA Bactericidal Toxin-Antitoxin System
Toxins 2020, 12(5), 329; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12050329 - 16 May 2020
Cited by 3 | Viewed by 1536
Abstract
MbcTA is a type II toxin/antitoxin (TA) system of Mycobacterium tuberculosis. The MbcT toxin triggers mycobacterial cell death in vitro and in vivo through the phosphorolysis of the essential metabolite NAD+ and its bactericidal activity is neutralized by physical interaction with [...] Read more.
MbcTA is a type II toxin/antitoxin (TA) system of Mycobacterium tuberculosis. The MbcT toxin triggers mycobacterial cell death in vitro and in vivo through the phosphorolysis of the essential metabolite NAD+ and its bactericidal activity is neutralized by physical interaction with its cognate antitoxin MbcA. Therefore, the MbcTA system appears as a promising target for the development of novel therapies against tuberculosis, through the identification of compounds able to antagonize or destabilize the MbcA antitoxin. Here, the expression of the mbcAT operon and its regulation were investigated. A dual fluorescent reporter system was developed, based on an integrative mycobacterial plasmid that encodes a constitutively expressed reporter, serving as an internal standard for monitoring mycobacterial gene expression, and an additional reporter, dependent on the promoter under investigation. This system was used both in M. tuberculosis and in the fast growing model species Mycobacterium smegmatis to: (i) assess the autoregulation of mbcAT; (ii) perform a genetic dissection of the mbcA promoter/operator region; and (iii) explore the regulation of mbcAT transcription from the mbcA promoter (PmbcA) in a variety of stress conditions, including in vivo in mice and in macrophages. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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Review

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Review
Targeting Type II Toxin–Antitoxin Systems as Antibacterial Strategies
Toxins 2020, 12(9), 568; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12090568 - 04 Sep 2020
Cited by 5 | Viewed by 1482
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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Review
The Fst/Ldr Family of Type I TA System Toxins: Potential Roles in Stress Response, Metabolism and Pathogenesis
Toxins 2020, 12(8), 474; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080474 - 25 Jul 2020
Cited by 4 | Viewed by 913
Abstract
The parpAD1 locus was the first type I toxin–antitoxin (TA) system described in Gram-positive bacteria and was later determined to be the founding member of a widely distributed family of plasmid- and chromosomally encoded TA systems. Indeed, homology searches revealed that the [...] Read more.
The parpAD1 locus was the first type I toxin–antitoxin (TA) system described in Gram-positive bacteria and was later determined to be the founding member of a widely distributed family of plasmid- and chromosomally encoded TA systems. Indeed, homology searches revealed that the toxin component, FstpAD1, is a member of the Fst/Ldr superfamily of peptide toxins found in both Gram-positive and Gram-negative bacteria. Regulation of the Fst and Ldr toxins is distinct in their respective Gram-positive and Gram-negative hosts, but the effects of ectopic over-expression are similar. While, the plasmid versions of these systems appear to play the canonical role of post-segregational killing stability mechanisms, the function of the chromosomal systems remains largely obscure. At least one member of the family has been suggested to play a role in pathogenesis in Staphylococcus aureus, while the regulation of several others appear to be tightly integrated with genes involved in sugar metabolism. After a brief discussion of the regulation and function of the foundational parpAD1 locus, this review will focus on the current information available on potential roles of the chromosomal homologs. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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Review
Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems
Toxins 2020, 12(6), 422; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12060422 - 26 Jun 2020
Cited by 1 | Viewed by 1556
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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