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Togo to the rescue : how a heroic husky saved the lives of children in Alaska
\"An inspiring picture book that explores the true story of Togo, the heroic Siberian Husky who traveled over 250 miles through a terrifying snowstorm to help deliver life-saving medicine to people in need, saving the lives of many\"-- Provided by publisher.
CHILDBOOK
Diphtheria Antitoxin Production and Procurement Practices and Challenges
Treatment of respiratory diphtheria requires prompt administration of equine diphtheria antitoxin (DAT) to neutralize circulating toxin. We conducted surveys of key procurement agencies and manufacturers currently engaged in DAT manufacturing or procurement, along with key informant interviews with developers of monoclonal antibodies. Our findings indicate that prices and availability of DAT vary and that prediction of demand is challenging for both manufacturers and procurement agencies. Substantial concerns were raised over the inability to obtain enough DAT to respond to increasing global outbreaks. Monoclonal antibody developers noted financial challenges in advancing their clinical and manufacturing progress.
Journal Article
TASmania: A bacterial Toxin-Antitoxin Systems database
Bacterial Toxin-Antitoxin systems (TAS) are involved in key biological functions including plasmid maintenance, defense against phages, persistence and virulence. They are found in nearly all phyla and classified into 6 different types based on the mode of inactivation of the toxin, with the type II TAS being the best characterized so far. We have herein developed a new in silico discovery pipeline named TASmania, which mines the >41K assemblies of the EnsemblBacteria database for known and uncharacterized protein components of type I to IV TAS loci. Our pipeline annotates the proteins based on a list of curated HMMs, which leads to >2.106 loci candidates, including orphan toxins and antitoxins, and organises the candidates in pseudo-operon structures in order to identify new TAS candidates based on a guilt-by-association strategy. In addition, we classify the two-component TAS with an unsupervised method on top of the pseudo-operon (pop) gene structures, leading to 1567 \"popTA\" models offering a more robust classification of the TAs families. These results give valuable clues in understanding the toxin/antitoxin modular structures and the TAS phylum specificities. Preliminary in vivo work confirmed six putative new hits in Mycobacterium tuberculosis as promising candidates. The TASmania database is available on the following server https://shiny.bioinformatics.unibe.ch/apps/tasmania/.
Journal Article
Bacterial retrons encode phage-defending tripartite toxin–antitoxin systems
Retrons are prokaryotic genetic retroelements encoding a reverse transcriptase that produces multi-copy single-stranded DNA
1
(msDNA). Despite decades of research on the biosynthesis of msDNA
2
, the function and physiological roles of retrons have remained unknown. Here we show that Retron-Sen2 of
Salmonella enterica
serovar Typhimurium encodes an accessory toxin protein, STM14_4640, which we renamed as RcaT. RcaT is neutralized by the reverse transcriptase–msDNA antitoxin complex, and becomes active upon perturbation of msDNA biosynthesis. The reverse transcriptase is required for binding to RcaT, and the msDNA is required for the antitoxin activity. The highly prevalent RcaT-containing retron family constitutes a new type of tripartite DNA-containing toxin–antitoxin system. To understand the physiological roles of such toxin–antitoxin systems, we developed toxin activation–inhibition conjugation (TAC-TIC), a high-throughput reverse genetics approach that identifies the molecular triggers and blockers of toxin–antitoxin systems. By applying TAC-TIC to Retron-Sen2, we identified multiple trigger and blocker proteins of phage origin. We demonstrate that phage-related triggers directly modify the msDNA, thereby activating RcaT and inhibiting bacterial growth. By contrast, prophage proteins circumvent retrons by directly blocking RcaT. Consistently, retron toxin–antitoxin systems act as abortive infection anti-phage defence systems, in line with recent reports
3
,
4
. Thus, RcaT retrons are tripartite DNA-regulated toxin–antitoxin systems, which use the reverse transcriptase–msDNA complex both as an antitoxin and as a sensor of phage protein activities.
Retron-Sen2 of
Salmonella
Typhimurium encodes a toxin and a reverse transcriptase, which, together with the Sen2 multi-copy single-stranded DNA synthesized by the reverse transcriptase make up a tripartite toxin–antitoxin system that functions in anti-phage defence.
Journal Article
sRNAs in bacterial type I and type III toxin-antitoxin systems
Toxin–antitoxin (TA) loci consist of two genes: a stable toxin whose overexpression kills the cell or causes growth stasis and an unstable antitoxin that neutralizes the toxin action. Currently, five TA systems are known. Here, we review type I and type III systems in which the antitoxins are regulatory RNAs. Type I antitoxins act by a base-pairing mechanism on toxin mRNAs. By contrast, type III antitoxins are RNA pseudoknots that bind their cognate toxins directly in an RNA–protein interaction. Whereas for a number of plasmid-encoded systems detailed information on structural requirements, kinetics of interaction with their targets and regulatory mechanisms employed by the antitoxin RNAs is available, the investigation of chromosomal systems is still in its infancy. Here, we summarize our current knowledge on that topic. Furthermore, we compare factors and conditions that induce antitoxins or toxins and different mechanisms of toxin action. Finally, we discuss biological roles for chromosome-encoded TA systems.
We summarize our current knowledge on small regulatory RNAs that act as antitoxins in plasmid or chromosome-encoded type I or type III toxin–antitoxin systems with regard to their mechanisms of action, structural requirements and kinetics of interaction with their targets, factors that regulate their expression, RNases that degrade them and the sRNA/target RNA complexes and, finally, their biological roles.
Journal Article
Structural insight into the distinct regulatory mechanism of the HEPN–MNT toxin-antitoxin system in Legionella pneumophila
HEPN–MNT, a type VII TA module, comprises the HEPN toxin and the MNT antitoxin, which acts as a nucleotidyltransferase that transfers the NMP moiety to the corresponding HEPN toxin, thereby interfering with its toxicity. Here, we report crystal structures of the
Legionella pneumophila
HEPN–MNT module, including HEPN, AMPylated HEPN, MNT, and the HEPN–MNT complex. Our structural analysis and biochemical assays, suggest that HEPN is a metal-dependent RNase and identify its active site residues. We also elucidate the oligomeric state of HEPN in solution. Interestingly,
L. pneumophila
MNT, which lacks a long C-terminal α4 helix, controls the toxicity of HEPN toxin via a distinct binding mode with HEPN. Finally, we propose a comprehensive regulatory mechanism of the
L. pneumophila
HEPN–MNT module based on structural and functional studies. These results provide insight into the type VII HEPN–MNT TA system.
HEPN–MNT is a bacterial type VII toxin-antitoxin (TA) system, comprising the HEPN toxin and the MNT antitoxin. Crystal structures and functional assays of the HEPN–MNT module suggest that HEPN is a metal-dependent RNase and identify its active site residues and regulatory mechanism.
Journal Article
One cannot rule them all: Are bacterial toxins-antitoxins druggable?
Type II (proteic) toxin–antitoxin (TA) operons are widely spread in bacteria and archaea. They are organized as operons in which, usually, the antitoxin gene precedes the cognate toxin gene. The antitoxin generally acts as a transcriptional self-repressor, whereas the toxin acts as a co-repressor, both proteins constituting a harmless complex. When bacteria encounter a stressful environment, TAs are triggered. The antitoxin protein is unstable and will be degraded by host proteases, releasing the free toxin to halt essential processes. The result is a cessation of cell growth or even death. Because of their ubiquity and the essential processes targeted, TAs have been proposed as good candidates for development of novel antimicrobials. We discuss here the possible druggability of TAs as antivirals and antibacterials, with focus on the potentials and the challenges that their use may find in the ‘real’ world. We present strategies to develop TAs as antibacterials in view of novel technologies, such as the use of very small molecules (fragments) as inhibitors of protein–protein interactions. Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair. Possible ways of delivery and formulation of Tas are also discussed.
We consider various approaches to develop the toxins of the type II family as possible candidates to drug discovery; druggability of toxins-antitoxins could be possible as antivirals. As antibacterials, they might be considered as druggable but delivery and formulation may not be simple so far.
Journal Article
Decoding the TAome and computational insights into parDE toxin-antitoxin systems in Pseudomonas aeruginosa
Toxin-antitoxin (TA) modules are widely found in the genomes of pathogenic bacteria. They regulate vital cellular functions like transcription, translation, and DNA replication, and are therefore essential to the survival of bacteria under stress. With a focus on the type II parDE modules, this study thoroughly examines TAome in Pseudomonas aeruginosa, a bacterium well-known for its adaptability and antibiotic resistance. We explored the TAome in three P. aeruginosa strains: ATCC 27,853, PAO1, and PA14, and found 15 type II TAs in ATCC 27,853, 12 in PAO1, and 13 in PA14, with significant variation in the associated mobile genetic elements. Five different parDE homologs were found by further TAome analysis in ATCC 27,853, and their relationships were confirmed by sequence alignments and precise genomic positions. After comparing these ParDE modules’ sequences to those of other pathogenic bacteria, it was discovered that they were conserved throughout many taxa, especially Proteobacteria. Nucleic acids were predicted as potential ligands for ParD antitoxins, whereas ParE toxins interacted with a wide range of small molecules, indicating a diverse functional repertoire. The interaction interfaces between ParDE TAs were clarified by protein-protein interaction networks and docking studies, which also highlighted important residues involved in binding. This thorough examination improves our understanding of the diversity, evolutionary dynamics, and functional significance of TA systems in P. aeruginosa, providing insights into their roles in bacterial physiology and pathogenicity.
Journal Article
Toxin–antitoxin systems and their role in disseminating and maintaining antimicrobial resistance
Abstract
Toxin–antitoxin systems (TAs) are ubiquitous among bacteria and play a crucial role in the dissemination and evolution of antibiotic resistance, such as maintaining multi-resistant plasmids and inducing persistence formation. Generally, activities of the toxins are neutralised by their conjugate antitoxins. In contrast, antitoxins are more liable to degrade under specific conditions such as stress, and free active toxins interfere with essential cellular processes including replication, translation and cell-wall synthesis. TAs have also been shown to be responsible for plasmid maintenance, stress management, bacterial persistence and biofilm formation. We discuss here the recent findings of these multifaceted TAs (type I–VI) and in particular examine the role of TAs in augmenting the dissemination and maintenance of multi-drug resistance in bacteria.
As antimicrobial resistance continues to escalate in Gram-negative bacteria, understanding the role of toxin–antitoxin systems in plasmid maintenance and inducing persistence becomes increasingly important.
Journal Article