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Microorganisms
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Bacterial Toxin–Antitoxin Systems
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Bacterial Toxin–Antitoxin Systems

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Molecular Microbiology and Immunology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 18475

Special Issue Editor

Dr. Muhammad Kamruzzaman

E-Mail Website
Guest Editor
Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia
Interests: toxin-antitoxin systems; plasmids; antibiotic resistance; bacterial stress responses; mobile genetic elements

Special Issue Information

Toxin–antitoxin systems (TASs) are widely distributed on bacterial genomes and are not essential to normal bacterial growth but are involved in the regulation of important bacterial cellular processes. TASs were originally discovered on bacterial plasmids in the 1980s as plasmid maintenance systems. Since then, thousands of TA loci have been identified on chromosomes, plasmids, and mobile elements in bacteria. A TAS typically consists of two gene loci encoding a stable toxin that induces cell death or arrests growth by inhibiting DNA replication, transcription, translation, and cell wall synthesis. A labile antitoxin neutralizes the toxin through binding to the toxin or other means. It is now known that TASs not only maintain genetic elements but are also involved in different physiological functions of bacteria, including stress responses, antibiotic tolerance, persister cell formation, biofilm formation, bacterial virulence, intestinal colonization, and phage predation. The involvement of TASs in different bacterial cellular processes has made them attractive therapeutic targets. Moreover, TASs present in conjugative antibiotic resistance and virulence plasmids participate in the maintenance of their stability and may play roles in their dissemination and epidemiology within bacterial species. Many TASs have yet to be identified and characterized, and the exact functions of most TASs remain unknown. 

We invite you to contribute to this Special Issue with an original research paper or a review article that sheds light on bacterial toxin–antitoxin systems. Topics of interest include the identification and characterization of novel TASs, the functions of TASs, and applications of TASs in biotechnology and drug design.

Dr. Muhammad Kamruzzaman
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • toxin–antitoxin systems
  • bacterial stress response
  • antibiotic resistance
  • mobile genetic elements
  • persister cell

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

3 pages, 152 KiB  
Editorial
Editorial for Special Issue “Bacterial Toxin-Antitoxin Systems”
by Muhammad Kamruzzaman
Microorganisms 2024, 12(1), 128; https://doi.org/10.3390/microorganisms12010128 - 08 Jan 2024
Viewed by 804
Abstract
Toxin antitoxin systems (TAS) are widely distributed in bacterial chromosomes as well as on mobile genetic elements [...] Full article
(This article belongs to the Special Issue Bacterial Toxin–Antitoxin Systems)

Research

Jump to: Editorial, Review

23 pages, 11089 KiB  
Article
Evolutionary Diversification of Host-Targeted Bartonella Effectors Proteins Derived from a Conserved FicTA Toxin-Antitoxin Module
by Tilman Schirmer, Tjaart A. P. de Beer, Stefanie Tamegger, Alexander Harms, Nikolaus Dietz, David M. Dranow, Thomas E. Edwards, Peter J. Myler, Isabelle Phan and Christoph Dehio
Microorganisms 2021, 9(8), 1645; https://doi.org/10.3390/microorganisms9081645 - 31 Jul 2021
Cited by 5 | Viewed by 2360
Abstract
Proteins containing a FIC domain catalyze AMPylation and other post-translational modifications (PTMs). In bacteria, they are typically part of FicTA toxin-antitoxin modules that control conserved biochemical processes such as topoisomerase activity, but they have also repeatedly diversified into host-targeted virulence factors. Among these, [...] Read more.
Proteins containing a FIC domain catalyze AMPylation and other post-translational modifications (PTMs). In bacteria, they are typically part of FicTA toxin-antitoxin modules that control conserved biochemical processes such as topoisomerase activity, but they have also repeatedly diversified into host-targeted virulence factors. Among these, Bartonella effector proteins (Beps) comprise a particularly diverse ensemble of FIC domains that subvert various host cellular functions. However, no comprehensive comparative analysis has been performed to infer molecular mechanisms underlying the biochemical and functional diversification of FIC domains in the vast Bep family. Here, we used X-ray crystallography, structural modelling, and phylogenetic analyses to unravel the expansion and diversification of Bep repertoires that evolved in parallel in three Bartonella lineages from a single ancestral FicTA toxin-antitoxin module. Our analysis is based on 99 non-redundant Bep sequences and nine crystal structures. Inferred from the conservation of the FIC signature motif that comprises the catalytic histidine and residues involved in substrate binding, about half of them represent AMP transferases. A quarter of Beps show a glutamate in a strategic position in the putative substrate binding pocket that would interfere with triphosphate-nucleotide binding but may allow binding of an AMPylated target for deAMPylation or another substrate to catalyze a distinct PTM. The β-hairpin flap that registers the modifiable target segment to the active site exhibits remarkable structural variability. The corresponding sequences form few well-defined groups that may recognize distinct target proteins. The binding of Beps to promiscuous FicA antitoxins is well conserved, indicating a role of the antitoxin to inhibit enzymatic activity or to serve as a chaperone for the FIC domain before translocation of the Bep into host cells. Taken together, our analysis indicates a remarkable functional plasticity of Beps that is mostly brought about by structural changes in the substrate pocket and the target dock. These findings may guide future structure–function analyses of the highly versatile FIC domains. Full article
(This article belongs to the Special Issue Bacterial Toxin–Antitoxin Systems)
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13 pages, 3067 KiB  
Article
Functional Characterization of the mazEF Toxin-Antitoxin System in the Pathogenic Bacterium Agrobacterium tumefaciens
by Wonho Choi, Yoshihiro Yamaguchi, Ji-Young Park, Sang-Hyun Park, Hyeok-Won Lee, Byung-Kwan Lim, Michael Otto, Masayori Inouye, Min-Ho Yoon and Jung-Ho Park
Microorganisms 2021, 9(5), 1107; https://doi.org/10.3390/microorganisms9051107 - 20 May 2021
Cited by 3 | Viewed by 2766
Abstract
Agrobacterium tumefaciens is a pathogen of various plants which transfers its own DNA (T-DNA) to the host plants. It is used for producing genetically modified plants with this ability. To control T-DNA transfer to the right place, toxin-antitoxin (TA) systems of A. tumefaciens [...] Read more.
Agrobacterium tumefaciens is a pathogen of various plants which transfers its own DNA (T-DNA) to the host plants. It is used for producing genetically modified plants with this ability. To control T-DNA transfer to the right place, toxin-antitoxin (TA) systems of A. tumefaciens were used to control the target site of transfer without any unintentional targeting. Here, we describe a toxin-antitoxin system, Atu0939 (mazE-at) and Atu0940 (mazF-at), in the chromosome of Agrobacterium tumefaciens. The toxin in the TA system has 33.3% identity and 45.5% similarity with MazF in Escherichia coli. The expression of MazF-at caused cell growth inhibition, while cells with MazF-at co-expressed with MazE-at grew normally. In vivo and in vitro assays revealed that MazF-at inhibited protein synthesis by decreasing the cellular mRNA stability. Moreover, the catalytic residue of MazF-at was determined to be the 24th glutamic acid using site-directed mutagenesis. From the results, we concluded that MazF-at is a type II toxin-antitoxin system and a ribosome-independent endoribonuclease. Here, we characterized a TA system in A. tumefaciens whose understanding might help to find its physiological function and to develop further applications. Full article
(This article belongs to the Special Issue Bacterial Toxin–Antitoxin Systems)
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12 pages, 2151 KiB  
Article
A Markerless Gene Deletion System in Streptococcus suis by Using the Copper-Inducible Vibrio parahaemolyticus YoeB Toxin as a Counterselectable Marker
by Chengkun Zheng, Man Wei, Jun Qiu and Jinquan Li
Microorganisms 2021, 9(5), 1095; https://doi.org/10.3390/microorganisms9051095 - 19 May 2021
Cited by 6 | Viewed by 2507
Abstract
Streptococcus suis is an important zoonotic pathogen causing severe infections in swine and humans. Induction of the Vibrio parahaemolyticus YoeB toxin in Escherichia coli resulted in cell death, leading to the speculation that YoeBVp can be a counterselectable marker. Herein, the counterselection [...] Read more.
Streptococcus suis is an important zoonotic pathogen causing severe infections in swine and humans. Induction of the Vibrio parahaemolyticus YoeB toxin in Escherichia coli resulted in cell death, leading to the speculation that YoeBVp can be a counterselectable marker. Herein, the counterselection potential of YoeBVp was assessed in S. suis. The yoeBVp gene was placed under the copper-induced promoter PcopA. The PcopA-yoeBVp construct was cloned into the S. suis-E. coli shuttle vector pSET2 and introduced into S. suis to assess the effect of YoeBVp expression on S. suis growth. Reverse transcription quantitative PCR showed that copper induced yoeBVp expression. Growth curve analyses and spot dilution assays showed that YoeBVp expression inhibited S. suis growth both in liquid media and on agar plates, revealing that YoeBVp has the potential to be a counterselectable marker for S. suis. A SCIY cassette comprising the spectinomycin-resistance gene and copper-induced yoeBVp was constructed. Using the SCIY cassette and peptide-induced competence, a novel two-step markerless gene deletion method was established for S. suis. Moreover, using the ΔperR mutant generated by this method, we demonstrated that PmtA, a ferrous iron and cobalt efflux pump in S. suis, was negatively regulated by the PerR regulator. Full article
(This article belongs to the Special Issue Bacterial Toxin–Antitoxin Systems)
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16 pages, 891 KiB  
Article
Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C
by Daniel Edelmann, Florian H. Leinberger, Nicole E. Schmid, Markus Oberpaul, Till F. Schäberle and Bork A. Berghoff
Microorganisms 2021, 9(5), 943; https://doi.org/10.3390/microorganisms9050943 - 27 Apr 2021
Cited by 9 | Viewed by 2204
Abstract
Bacterial chromosomes harbor toxin-antitoxin (TA) systems, some of which are implicated in the formation of multidrug-tolerant persister cells. In Escherichia coli, toxin TisB from the tisB/istR-1 TA system depolarizes the inner membrane and causes ATP depletion, which presumably favors persister [...] Read more.
Bacterial chromosomes harbor toxin-antitoxin (TA) systems, some of which are implicated in the formation of multidrug-tolerant persister cells. In Escherichia coli, toxin TisB from the tisB/istR-1 TA system depolarizes the inner membrane and causes ATP depletion, which presumably favors persister formation. Transcription of tisB is induced upon DNA damage due to activation of the SOS response by LexA degradation. Transcriptional activation of tisB is counteracted on the post-transcriptional level by structural features of tisB mRNA and RNA antitoxin IstR-1. Deletion of the regulatory RNA elements (mutant Δ1-41 ΔistR) uncouples TisB expression from LexA-dependent SOS induction and causes a ‘high persistence’ (hip) phenotype upon treatment with different antibiotics. Here, we demonstrate by the use of fluorescent reporters that TisB overexpression in mutant Δ1-41 ΔistR inhibits cellular processes, including the expression of SOS genes. The failure in SOS gene expression does not affect the hip phenotype upon treatment with the fluoroquinolone ciprofloxacin, likely because ATP depletion avoids strong DNA damage. By contrast, Δ1-41 ΔistR cells are highly susceptible to the DNA cross-linker mitomycin C, likely because the expression of SOS-dependent repair systems is impeded. Hence, the hip phenotype of the mutant is conditional and strongly depends on the DNA-damaging agent. Full article
(This article belongs to the Special Issue Bacterial Toxin–Antitoxin Systems)
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Review

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23 pages, 1255 KiB  
Review
Biological Functions of Type II Toxin-Antitoxin Systems in Bacteria
by Muhammad Kamruzzaman, Alma Y. Wu and Jonathan R. Iredell
Microorganisms 2021, 9(6), 1276; https://doi.org/10.3390/microorganisms9061276 - 11 Jun 2021
Cited by 54 | Viewed by 6474
Abstract
After the first discovery in the 1980s in F-plasmids as a plasmid maintenance system, a myriad of toxin-antitoxin (TA) systems has been identified in bacterial chromosomes and mobile genetic elements (MGEs), including plasmids and bacteriophages. TA systems are small genetic modules that encode [...] Read more.
After the first discovery in the 1980s in F-plasmids as a plasmid maintenance system, a myriad of toxin-antitoxin (TA) systems has been identified in bacterial chromosomes and mobile genetic elements (MGEs), including plasmids and bacteriophages. TA systems are small genetic modules that encode a toxin and its antidote and can be divided into seven types based on the nature of the antitoxin molecules and their mechanism of action to neutralise toxins. Among them, type II TA systems are widely distributed in chromosomes and plasmids and the best studied so far. Maintaining genetic material may be the major function of type II TA systems associated with MGEs, but the chromosomal TA systems contribute largely to functions associated with bacterial physiology, including the management of different stresses, virulence and pathogenesis. Due to growing interest in TA research, extensive work has been conducted in recent decades to better understand the physiological roles of these chromosomally encoded modules. However, there are still controversies about some of the functions associated with different TA systems. This review will discuss the most current findings and the bona fide functions of bacterial type II TA systems. Full article
(This article belongs to the Special Issue Bacterial Toxin–Antitoxin Systems)
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