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Microorganisms
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Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria
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Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria

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

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 14601

Special Issue Editors

Prof. Camilla Lazzi

E-Mail Website
Guest Editor
University of Parma, Food and Drug Department, Parma, Italy
Interests: lactic acid bacteria; fermentation; food microbiology; waste valorization; bacteria metabolism; microbial dynamics; toxin-antitoxin systems; gene expression studies
Dr. Claudia Folli

E-Mail Website
Guest Editor
University of Parma, Food and Drug Department, Parma, Italy
Interests: protein structure; protein-protein interaction; structure-function relationship; gene expression regulation; molecular microbiology; food biochemistry

Special Issue Information

Dear Colleagues,

Toxin–antitoxin (TA) systems,  widely distributed in bacterial plasmids and chromosomes, represent versatile stress-response mechanisms able to regulate cell growth and death. TA systems are composed of a stable toxin, a peptide or a protein with the capacity to induce cell death or dormancy, and an antitoxin, a protein or a non-coding RNA, which neutralizes the toxin and is liable to degrade under specific conditions. To date, TA systems are grouped in different types, based on the molecular nature and the mechanism of action of the antitoxin molecule.

TA systems are widespread in pathogenic and non-pathogenic microorganisms, suggesting their relevance in different ecosystems. In pathogenic bacteria, these systems are thought to play a role in bacterial virulence, persistence and biofilm formation. In addition, TA systems can represent alternative targets for antimicrobial drugs.

Recently, various TA systems have been identified and characterized in non-pathogenic bacteria, such as lactic acid bacteria. This group of microorganisms plays important roles in different habitats (food, feed, plant, and human cavities) and are extensively exploited in biotechnological processes and industrial applications. The high abundance of TA systems in the genomes of non-pathogenic bacteria raises the question of their role in regulating the activity of these bacteria of great interest for human health and industrial productions.

In this Special Issue, we invite contributions concerning new aspects related to all types of TA systems identified in pathogenic and non-pathogenic bacteria.

Prof. Camilla Lazzi
Dr. Claudia Folli
Guest Editors

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
  • bacteria
  • stress-response
  • dormancy
  • adaptation
  • cell death
  • cellular processes

Published Papers (7 papers)

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Research

14 pages, 2331 KiB  
Article
Insights into the Neutralization and DNA Binding of Toxin–Antitoxin System ParESO-CopASO by Structure-Function Studies
by Juan Zhou, Xue-Jian Du, Ying Liu, Zeng-Qiang Gao, Zhi Geng, Yu-Hui Dong and Heng Zhang
Microorganisms 2021, 9(12), 2506; https://doi.org/10.3390/microorganisms9122506 - 03 Dec 2021
Cited by 3 | Viewed by 1549
Abstract
ParESO-CopASO is a new type II toxin–antitoxin (TA) system in prophage CP4So that plays an essential role in circular CP4So maintenance after the excision in Shewanella oneidensis. The toxin ParESO severely inhibits cell growth, while CopASO functions [...] Read more.
ParESO-CopASO is a new type II toxin–antitoxin (TA) system in prophage CP4So that plays an essential role in circular CP4So maintenance after the excision in Shewanella oneidensis. The toxin ParESO severely inhibits cell growth, while CopASO functions as an antitoxin to neutralize ParESO toxicity through direct interactions. However, the molecular mechanism of the neutralization and autoregulation of the TA operon transcription remains elusive. In this study, we determined the crystal structure of a ParESO-CopASO complex that adopted an open V-shaped heterotetramer with the organization of ParESO-(CopASO)2-ParESO. The structure showed that upon ParESO binding, the intrinsically disordered C-terminal domain of CopASO was induced to fold into a partially ordered conformation that bound into a positively charged and hydrophobic groove of ParESO. Thermodynamics analysis showed the DNA-binding affinity of CopASO was remarkably higher than that of the purified TA complex, accompanied by the enthalpy change reversion from an exothermic reaction to an endothermic reaction. These results suggested ParESO acts as a de-repressor of the TA operon transcription at the toxin:antitoxin level of 1:1. Site-directed mutagenesis of ParESO identified His91 as the essential residue for its toxicity by cell toxicity assays. Our structure-function studies therefore elucidated the transcriptional regulation mechanism of the ParESO-CopASO pair, and may help to understand the regulation of CP4So maintenance in S. oneidensis. Full article
(This article belongs to the Special Issue Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria)
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9 pages, 1253 KiB  
Article
Correlation between mazEF Toxin-Antitoxin System Expression and Methicillin Susceptibility in Staphylococcus aureus and Its Relation to Biofilm-Formation
by Aya Abd El rahman, Yasmine El kholy and Rania Y. Shash
Microorganisms 2021, 9(11), 2274; https://doi.org/10.3390/microorganisms9112274 - 31 Oct 2021
Cited by 4 | Viewed by 1584
Abstract
Methicillin resistance in Staphylococcus aureus has become prevalent globally. Moreover, biofilm-formation makes it more difficult to eradicate bacteria by antibiotics. The mazEF toxin-antitoxin system encodes for mazF, which acts as an endoribonuclease that cleaves cellular mRNAs at specific sequence motifs (ACA), and mazE, [...] Read more.
Methicillin resistance in Staphylococcus aureus has become prevalent globally. Moreover, biofilm-formation makes it more difficult to eradicate bacteria by antibiotics. The mazEF toxin-antitoxin system encodes for mazF, which acts as an endoribonuclease that cleaves cellular mRNAs at specific sequence motifs (ACA), and mazE, which opposes the mazF action. Our goal was to detect mazEF expression in methicillin-resistant S. aureus (MRSA) isolates compared with methicillin-sensitive S. aureus (MSSA) isolates and determine its relation to methicillin susceptibility as well as biofilm-formation. According to their susceptibility to cefoxitin disks, 100 S. aureus isolates obtained from patients admitted to Cairo University Hospitals were categorized into 50 MSSA and 50 MRSA according to their susceptibility to cefoxitin disks (30 µg). Antimicrobial susceptibility and biofilm-formation were investigated using the disk diffusion method and tissue culture plate method, respectively. Finally, using real-time PCR, mazEF expression was estimated and correlated to methicillin susceptibility and biofilm formation. Both MRSA and MSSA isolates showed the best sensitivity results with linezolid and gentamicin, where about 88% of MRSA isolates and 96% of MSSA isolates were sensitive to linezolid while 76% of MRSA isolates and 84% of MSSA isolates were sensitive to gentamicin. MRSA isolates were significantly more able to form biofilm than MSSA isolates (p-value = 0.037). The mazEF expression was significantly correlated to methicillin resistance in S. aureus (p-value < 0.001), but not to biofilm-formation. Full article
(This article belongs to the Special Issue Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria)
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16 pages, 1804 KiB  
Article
Interactions of the Streptococcus pneumoniae Toxin-Antitoxin RelBE Proteins with Their Target DNA
by Inmaculada Moreno-Córdoba, Wai-Ting Chan, Concha Nieto and Manuel Espinosa
Microorganisms 2021, 9(4), 851; https://doi.org/10.3390/microorganisms9040851 - 15 Apr 2021
Cited by 2 | Viewed by 1976
Abstract
Type II bacterial toxin-antitoxin (TA) systems are found in most bacteria, archaea, and mobile genetic elements. TAs are usually found as a bi-cistronic operon composed of an unstable antitoxin and a stable toxin that targets crucial cellular functions like DNA supercoiling, cell-wall synthesis [...] Read more.
Type II bacterial toxin-antitoxin (TA) systems are found in most bacteria, archaea, and mobile genetic elements. TAs are usually found as a bi-cistronic operon composed of an unstable antitoxin and a stable toxin that targets crucial cellular functions like DNA supercoiling, cell-wall synthesis or mRNA translation. The type II RelBE system encoded by the pathogen Streptococcus pneumoniae is highly conserved among different strains and participates in biofilm formation and response to oxidative stress. Here, we have analyzed the participation of the RelB antitoxin and the RelB:RelE protein complex in the self-regulation of the pneumococcal relBE operon. RelB acted as a weak repressor, whereas RelE performed the role of a co-repressor. By DNA footprinting experiments, we show that the proteins bind to a region that encompasses two palindromic sequences that are located around the −10 sequences of the single promoter that directs the synthesis of the relBE mRNA. High-resolution footprinting assays showed the distribution of bases whose deoxyriboses are protected by the bound proteins, demonstrating that RelB and RelB:RelE contacted the DNA backbone on one face of the DNA helix and that these interactions extended beyond the palindromic sequences. Our findings suggest that the binding of the RelBE proteins to its DNA target would lead to direct inhibition of the binding of the host RNA polymerase to the relBE promoter. Full article
(This article belongs to the Special Issue Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria)
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16 pages, 10492 KiB  
Article
Identification of a Toxin–Antitoxin System That Contributes to Persister Formation by Reducing NAD in Pseudomonas aeruginosa
by Jingyi Zhou, Shouyi Li, Haozhou Li, Yongxin Jin, Fang Bai, Zhihui Cheng and Weihui Wu
Microorganisms 2021, 9(4), 753; https://doi.org/10.3390/microorganisms9040753 - 02 Apr 2021
Cited by 11 | Viewed by 2719
Abstract
Bacterial persisters are slow-growing or dormant cells that are highly tolerant to bactericidal antibiotics and contribute to recalcitrant and chronic infections. Toxin/antitoxin (TA) systems play important roles in controlling persister formation. Here, we examined the roles of seven predicted type II TA systems [...] Read more.
Bacterial persisters are slow-growing or dormant cells that are highly tolerant to bactericidal antibiotics and contribute to recalcitrant and chronic infections. Toxin/antitoxin (TA) systems play important roles in controlling persister formation. Here, we examined the roles of seven predicted type II TA systems in the persister formation of a Pseudomonas aeruginosa wild-type strain PA14. Overexpression of a toxin gene PA14_51010 or deletion of the cognate antitoxin gene PA14_51020 increased the bacterial tolerance to antibiotics. Co-overexpression of PA14_51010 and PA14_51020 or simultaneous deletion of the two genes resulted in a wild-type level survival rate following antibiotic treatment. The two genes were located in the same operon that was repressed by PA14_51020. We further demonstrated the interaction between PA14_51010 and PA14_51020. Sequence analysis revealed that PA14_51010 contained a conserved RES domain. Overexpression of PA14_51010 reduced the intracellular level of nicotinamide adenine dinucleotide (NAD+). Mutation of the RES domain abolished the abilities of PA14_51010 in reducing NAD+ level and promoting persister formation. In addition, overproduction of NAD+ by mutation in an nrtR gene counteracted the effect of PA14_51010 overexpression in promoting persister formation. In combination, our results reveal a novel TA system that contributes to persister formation through reducing the intracellular NAD+ level in P. aeruginosa. Full article
(This article belongs to the Special Issue Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria)
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15 pages, 2988 KiB  
Article
Genome Sequencing of five Lacticaseibacillus Strains and Analysis of Type I and II Toxin-Antitoxin System Distribution
by Alessia Levante, Camilla Lazzi, Giannis Vatsellas, Dimitris Chatzopoulos, Vasilis S. Dionellis, Periklis Makrythanasis, Erasmo Neviani and Claudia Folli
Microorganisms 2021, 9(3), 648; https://doi.org/10.3390/microorganisms9030648 - 21 Mar 2021
Cited by 8 | Viewed by 2204
Abstract
The analysis of bacterial genomes is a potent tool to investigate the distribution of specific traits related to the ability of surviving in particular environments. Among the traits associated with the adaptation to hostile conditions, toxin–antitoxin (TA) systems have recently gained attention in [...] Read more.
The analysis of bacterial genomes is a potent tool to investigate the distribution of specific traits related to the ability of surviving in particular environments. Among the traits associated with the adaptation to hostile conditions, toxin–antitoxin (TA) systems have recently gained attention in lactic acid bacteria. In this work, genome sequences of Lacticaseibacillus strains of dairy origin were compared, focusing on the distribution of type I TA systems homologous to Lpt/RNAII and of the most common type II TA systems. A high number of TA systems have been identified spread in all the analyzed strains, with type I TA systems mainly located on plasmid DNA. The type II TA systems identified in these strains highlight the diversity of encoded toxins and antitoxins and their organization. This study opens future perspectives on the use of genomic data as a resource for the study of TA systems distribution and prevalence in microorganisms of industrial relevance. Full article
(This article belongs to the Special Issue Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria)
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10 pages, 1893 KiB  
Article
Toxin-Activating Stapled Peptides Discovered by Structural Analysis Were Identified as New Therapeutic Candidates That Trigger Antibacterial Activity against Mycobacterium tuberculosis in the Mycobacterium smegmatis Model
by Sung-Min Kang, Heejo Moon, Sang-Woo Han, Byeong Wook Kim, Do-Hee Kim, Byeong Moon Kim and Bong-Jin Lee
Microorganisms 2021, 9(3), 568; https://doi.org/10.3390/microorganisms9030568 - 10 Mar 2021
Cited by 7 | Viewed by 1991
Abstract
The structure-function relationships of toxin-antitoxin (TA) systems from Mycobacterium tuberculosis have prompted the development of novel and effective antimicrobial agents that selectively target this organism. The artificial activation of toxins by peptide inhibitors can lead to the growth arrest and eventual death of [...] Read more.
The structure-function relationships of toxin-antitoxin (TA) systems from Mycobacterium tuberculosis have prompted the development of novel and effective antimicrobial agents that selectively target this organism. The artificial activation of toxins by peptide inhibitors can lead to the growth arrest and eventual death of bacterial cells. Optimizing candidate peptides by hydrocarbon α-helix stapling based on structural information from the VapBC TA system and in vitro systematic validation led to V26-SP-8, a VapC26 activator of M. tuberculosis. This compound exhibited highly enhanced activity and cell permeability owing to the stabilizing helical propensity of the peptide. These characteristics will increase its efficacy against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Similar approaches utilizing structural and biochemical information for new antibiotic targets opens a new era for developing TB therapies. Full article
(This article belongs to the Special Issue Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria)
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17 pages, 2941 KiB  
Article
The Disordered C-Terminus of the Chaperone DnaK Increases the Competitive Fitness of Pseudomonas putida and Facilitates the Toxicity of GraT
by Sirli Rosendahl, Andres Ainelo and Rita Hõrak
Microorganisms 2021, 9(2), 375; https://doi.org/10.3390/microorganisms9020375 - 13 Feb 2021
Cited by 5 | Viewed by 1637
Abstract
Chaperone proteins are crucial for proper protein folding and quality control, especially when cells encounter stress caused by non-optimal temperatures. DnaK is one of such essential chaperones in bacteria. Although DnaK has been well characterized, the function of its intrinsically disordered C-terminus [...] Read more.
Chaperone proteins are crucial for proper protein folding and quality control, especially when cells encounter stress caused by non-optimal temperatures. DnaK is one of such essential chaperones in bacteria. Although DnaK has been well characterized, the function of its intrinsically disordered C-terminus has remained enigmatic as the deletion of this region has been shown to either enhance or reduce its protein folding ability. We have shown previously that DnaK interacts with toxin GraT of the GraTA toxin-antitoxin system in Pseudomonas putida. Interestingly, the C-terminal truncation of DnaK was shown to alleviate GraT-caused growth defects. Here, we aim to clarify the importance of DnaK in GraT activity. We show that DnaK increases GraT toxicity, and particularly important is the negatively charged motif in the DnaK C-terminus. Given that GraT has an intrinsically disordered N-terminus, the assistance of DnaK is probably needed for re-modelling the toxin structure. We also demonstrate that the DnaK C-terminal negatively charged motif contributes to the competitive fitness of P. putida at both high and optimal growth temperatures. Thus, our data suggest that the disordered C-terminal end of DnaK enhances the chaperone functionality. Full article
(This article belongs to the Special Issue Toxin–Antitoxin Systems in Pathogenic and Non-Pathogenic Bacteria)
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