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Toxins Jan 2014Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are... (Review)
Review
Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are widely spread in bacterial and archaeal genomes. TA systems have been assigned many functions, ranging from persistence to DNA stabilization or protection against mobile genetic elements. They are classified in five types, depending on the nature and mode of action of the antitoxin. In type I and III, antitoxins are RNAs that either inhibit the synthesis of the toxin or sequester it. In type II, IV and V, antitoxins are proteins that either sequester, counterbalance toxin activity or inhibit toxin synthesis. In addition to these interactions between the antitoxin and toxin components (RNA-RNA, protein-protein, RNA-protein), TA systems interact with a variety of cellular factors, e.g., toxins target essential cellular components, antitoxins are degraded by RNAses or ATP-dependent proteases. Hence, TA systems have the capacity to interact with each other at different levels. In this review, we will discuss the different interactions in which TA systems are involved and their implications in TA system functions and evolution.
Topics: Antitoxins; Bacterial Proteins; DNA, Bacterial; Escherichia coli; Protein Interaction Domains and Motifs; Toxins, Biological; Transcriptional Activation
PubMed: 24434905
DOI: 10.3390/toxins6010304 -
Clinical Infectious Diseases : An... Oct 2022Bacillus anthracis is a high-priority threat agent because of its widespread availability, easy dissemination, and ability to cause substantial morbidity and mortality....
BACKGROUND
Bacillus anthracis is a high-priority threat agent because of its widespread availability, easy dissemination, and ability to cause substantial morbidity and mortality. Although timely and appropriate antimicrobial therapy can reduce morbidity and mortality, the role of adjunctive therapies continues to be explored.
METHODS
We searched 11 databases for articles that report use of anthrax antitoxins in treatment or prevention of systemic anthrax disease published through July 2019. We identified other data sources through reference search and communication with experts. We included English-language studies on antitoxin products with approval by the US Food and Drug Administration (FDA) for anthrax in humans, nonhuman primates, and rabbits. Two researchers independently reviewed studies for inclusion and abstracted relevant data.
RESULTS
We abstracted data from 12 publications and 2 case reports. All 3 FDA-approved anthrax antitoxins demonstrated significant improvement in survival as monotherapy over placebo in rabbits and nonhuman primates. No study found significant improvement in survival with combination antitoxin and antimicrobial therapy compared to antimicrobial monotherapy. Case reports and case series described 25 patients with systemic anthrax disease treated with antitoxins; 17 survived. Animal studies that used antitoxin monotherapy as postexposure prophylaxis (PEP) demonstrated significant improvement in survival over placebo, with greatest improvements coming with early administration.
CONCLUSIONS
Limited human and animal evidence indicates that adjunctive antitoxin treatment may improve survival from systemic anthrax infection. Antitoxins may also provide an alternative therapy to antimicrobials for treatment or PEP during an intentional anthrax incident that could involve a multidrug-resistant B. anthracis strain.
Topics: Animals; Anthrax; Anti-Bacterial Agents; Anti-Infective Agents; Antitoxins; Bacillus anthracis; Humans; Primates; Rabbits
PubMed: 36251559
DOI: 10.1093/cid/ciac532 -
Toxins Jul 2016Toxin-antitoxin (TA) systems are prevalent in bacteria and archaea. Although not essential for normal cell growth, TA systems are implicated in multiple cellular... (Review)
Review
Toxin-antitoxin (TA) systems are prevalent in bacteria and archaea. Although not essential for normal cell growth, TA systems are implicated in multiple cellular functions associated with survival under stress conditions. Clinical strains of bacteria are currently causing major human health problems as a result of their multidrug resistance, persistence and strong pathogenicity. Here, we present a review of the TA systems described to date and their biological role in human pathogens belonging to the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) and others of clinical relevance (Escherichia coli, Burkholderia spp., Streptococcus spp. and Mycobacterium tuberculosis). Better understanding of the mechanisms of action of TA systems will enable the development of new lines of treatment for infections caused by the above-mentioned pathogens.
Topics: Animals; Anti-Bacterial Agents; Antitoxins; Bacteria; Bacterial Infections; Bacterial Toxins; Drug Resistance, Bacterial; Host-Pathogen Interactions; Humans; Virulence
PubMed: 27447671
DOI: 10.3390/toxins8070227 -
Health Security 2015Concern about use of anthrax as a bioweapon prompted development of novel anthrax antitoxins for treatment. Clinical guidelines for the treatment of anthrax recommend... (Review)
Review
Concern about use of anthrax as a bioweapon prompted development of novel anthrax antitoxins for treatment. Clinical guidelines for the treatment of anthrax recommend antitoxin therapy in combination with intravenous antimicrobials; however, a large-scale or mass anthrax incident may exceed antitoxin availability and create a need for judicious antitoxin use. We conducted a systematic review of antitoxin treatment of inhalation anthrax in humans and experimental animals to inform antitoxin recommendations during a large-scale or mass anthrax incident. A comprehensive search of 11 databases and the FDA website was conducted to identify relevant animal studies and human reports: 28 animal studies and 3 human cases were identified. Antitoxin monotherapy at or shortly after symptom onset demonstrates increased survival compared to no treatment in animals. With early treatment, survival did not differ between antimicrobial monotherapy and antimicrobial-antitoxin therapy in nonhuman primates and rabbits. With delayed treatment, antitoxin-antimicrobial treatment increased rabbit survival. Among human cases, addition of antitoxin to combination antimicrobial treatment was associated with survival in 2 of the 3 cases treated. Despite the paucity of human data, limited animal data suggest that adjunctive antitoxin therapy may improve survival. Delayed treatment studies suggest improved survival with combined antitoxin-antimicrobial therapy, although a survival difference compared with antimicrobial therapy alone was not demonstrated statistically. In a mass anthrax incident with limited antitoxin supplies, antitoxin treatment of individuals who have not demonstrated a clinical benefit from antimicrobials, or those who present with more severe illness, may be warranted. Additional pathophysiology studies are needed, and a point-of-care assay correlating toxin levels with clinical status may provide important information to guide antitoxin use during a large-scale anthrax incident.
Topics: Administration, Intravenous; Animals; Anthrax; Anti-Bacterial Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Bacterial; Antitoxins; Bioterrorism; Drug Therapy, Combination; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Mass Casualty Incidents; Rabbits; Respiratory Tract Infections
PubMed: 26690378
DOI: 10.1089/hs.2015.0032 -
Molecular Cell Jul 2023Modification of nucleic acids by ADP-ribosylation is catalyzed by various ADP-ribosyltransferases, including the DarT enzyme. The latter is part of the bacterial...
Modification of nucleic acids by ADP-ribosylation is catalyzed by various ADP-ribosyltransferases, including the DarT enzyme. The latter is part of the bacterial toxin-antitoxin (TA) system DarTG, which was shown to provide control of DNA replication and bacterial growth as well as protection against bacteriophages. Two subfamilies have been identified, DarTG1 and DarTG2, which are distinguished by their associated antitoxins. While DarTG2 catalyzes reversible ADP-ribosylation of thymidine bases employing a macrodomain as antitoxin, the DNA ADP-ribosylation activity of DarTG1 and the biochemical function of its antitoxin, a NADAR domain, are as yet unknown. Using structural and biochemical approaches, we show that DarT1-NADAR is a TA system for reversible ADP-ribosylation of guanosine bases. DarT1 evolved the ability to link ADP-ribose to the guanine amino group, which is specifically hydrolyzed by NADAR. We show that guanine de-ADP-ribosylation is also conserved among eukaryotic and non-DarT-associated NADAR members, indicating a wide distribution of reversible guanine modifications beyond DarTG systems.
Topics: Guanosine; ADP-Ribosylation; ADP Ribose Transferases; Eukaryotic Cells; Antitoxins; Adenosine Diphosphate Ribose
PubMed: 37390817
DOI: 10.1016/j.molcel.2023.06.013 -
Japanese Journal of Infectious Diseases May 2020Clostridium species are gram-positive, spore-forming, anaerobic rods normally found in the soil and gastrointestinal tract of humans and animals. Spontaneous sepsis due... (Review)
Review
Clostridium species are gram-positive, spore-forming, anaerobic rods normally found in the soil and gastrointestinal tract of humans and animals. Spontaneous sepsis due to C. perfringens is not caused by injury, which sets it apart from the classical gas gangrene that typically follows trauma. Spontaneous C. perfringens sepsis often develops as a rapidly progressive intravascular hemolysis and metabolic acidosis, with high mortality rates of over 70% with standard intensive care. In such cases, alpha toxin secreted by C. perfringens is considered the main toxin responsible for intravascular hemolysis, disseminated intravascular coagulopathy, and multiple organ failure. Theta-toxin causes a cytokine cascade, which results in peripheral vasodilation similar to that seen in septic shock. For C. perfringens infections, antibiotics, such as high-dose penicillin, and surgical drainage as early as possible are the principal treatments of choice. However, considering the current mortality rate of sepsis, outcomes have not improved with the current standard treatment for C. perfringens infections. Monoclonal antibody against theta toxin in combination with gas gangrene antitoxin presents a promising therapeutic option.
Topics: Anti-Bacterial Agents; Antitoxins; Clostridium Infections; Humans; Sepsis
PubMed: 31875607
DOI: 10.7883/yoken.JJID.2019.382 -
Toxins Dec 2022Botulism is a low incidence but potentially fatal infectious disease caused by neurotoxins produced mainly by . There are different routes of acquisition, food-borne and...
BACKGROUND
Botulism is a low incidence but potentially fatal infectious disease caused by neurotoxins produced mainly by . There are different routes of acquisition, food-borne and infant/intestinal being the most frequent presentation, and antitoxin is the treatment of choice in all cases. In Spain, botulism is under surveillance, and case reporting is mandatory.
METHODS
This retrospective study attempts to provide a more complete picture of the epidemiology of botulism in Spain from 1997 to 2019 and an assessment of the treatment, including the relationship between a delay in antitoxin administration and the length of hospitalization using the Cox proportional hazards test and Kruskal-Wallis test, and an approach to the frequency of adverse events, issues for which no previous national data have been published.
RESULTS
Eight of the 44 outbreaks were associated with contaminated commercial foods involving ≤7 cases/outbreak; preserved vegetables were the main source of infection, followed by fish products; early antitoxin administration significantly reduces the hospital stay, and adverse reactions to the antitoxin affect around 3% of treated cases.
Topics: Animals; Botulism; Antitoxins; Retrospective Studies; Spain; Clostridium botulinum; Botulinum Antitoxin
PubMed: 36668823
DOI: 10.3390/toxins15010002 -
Nature Communications Jul 2022Toxin-antitoxin (TA) systems are ubiquitous genetic modules in bacteria and archaea. Here, we perform structural and biochemical characterization of the Legionella...
Toxin-antitoxin (TA) systems are ubiquitous genetic modules in bacteria and archaea. Here, we perform structural and biochemical characterization of the Legionella pneumophila effector Lpg2370, demonstrating that it is a Ser/Thr kinase. Together with two upstream genes, lpg2370 constitutes the tripartite HipBST TA. Notably, the toxin Lpg2370 (HipT) and the antitoxin Lpg2369 (HipS) correspond to the C-terminus and N-terminus of HipA from HipBA TA, respectively. By determining crystal structures of autophosphorylated HipT, its complex with AMP-PNP, and the structure of HipT-HipS complex, we identify residues in HipT critical for ATP binding and those contributing to its interactions with HipS. Structural analysis reveals that HipS binding induces a loop-to-helix shift in the P-loop of HipT, leading to the blockage of ATP binding and inhibition of the kinase activity. These findings establish the L. pneumophila effector Lpg2370 as the HipBST TA toxin and elucidate the molecular basis for HipT neutralization in HipBST TA.
Topics: Adenosine Triphosphate; Antitoxins; Bacterial Proteins; Bacterial Toxins; Legionella pneumophila; Toxin-Antitoxin Systems
PubMed: 35882877
DOI: 10.1038/s41467-022-32049-x -
Current Genetics May 2016Toxin-antitoxin (TA) modules regulate metabolism and viability of bacteria and archaea. In type II TA systems these functions are generally thought to be performed by... (Review)
Review
Toxin-antitoxin (TA) modules regulate metabolism and viability of bacteria and archaea. In type II TA systems these functions are generally thought to be performed by two small proteins. However, evidence is increasing that the toxins are much more diverse and can form multi-domain proteins. Recently, we published a novel type II TA system in which toxin and antitoxin are covalently linked into a single polypeptide chain. In this review we summarize the current knowledge on these elongated toxin homologs and provide perspectives for future study.
Topics: Animals; Antitoxins; Toxins, Biological
PubMed: 26597447
DOI: 10.1007/s00294-015-0541-7 -
Toxins Jul 2021Bacterial 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... (Review)
Review
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 - or -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 -encoded membrane peptides that belong to the /SprF1 type I TA system expressed in and discusses the putative membrane interactions allowing the lysis of competing bacteria and host cells.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Gene Expression Regulation, Bacterial; Gram-Positive Bacteria; RNA, Bacterial; RNA, Messenger; Ribonucleases; Staphylococcal Infections; Staphylococcus aureus; Toxin-Antitoxin Systems
PubMed: 34357962
DOI: 10.3390/toxins13070490