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Toxins Jan 2021Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal... (Review)
Review
Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal dystonia, despite short-term clinical benefits and the risks of adverse effects. To cater for the high demand across various medical specialties, at least six US Food and Drug Administration (FDA)-approved formulations of BoNT are currently available for diverse labelled indications. The toxo-pharmacological properties of these formulations are not uniform and thus should not be used interchangeably. Synthetic BoNTs and BoNTs from non-clostridial sources are not far from clinical use. Moreover, the study of mutations in naturally occurring toxins has led to modulation in the toxo-pharmacokinetic properties of BoNTs, including the duration and potency. We present an overview of the toxo-pharmacology of conventional and novel BoNT preparations, including those awaiting imminent translation from the laboratory to the clinic.
Topics: Bacterial Toxins; Botulinum Toxins; Drug Compounding; Drug Development; Drug Prescriptions; Humans; Nervous System Diseases; Neuromuscular Agents; Neuromuscular Junction; Recombinant Proteins
PubMed: 33466571
DOI: 10.3390/toxins13010058 -
Microbiology (Reading, England) Mar 2022Pore-forming toxins (PFTs) are widely distributed in both Gram-negative and Gram-positive bacteria. PFTs can act as virulence factors that bacteria utilise in...
Pore-forming toxins (PFTs) are widely distributed in both Gram-negative and Gram-positive bacteria. PFTs can act as virulence factors that bacteria utilise in dissemination and host colonisation or, alternatively, they can be employed to compete with rival microbes in polymicrobial niches. PFTs transition from a soluble form to become membrane-embedded by undergoing large conformational changes. Once inserted, they perforate the membrane, causing uncontrolled efflux of ions and/or nutrients and dissipating the protonmotive force (PMF). In some instances, target cells intoxicated by PFTs display additional effects as part of the cellular response to pore formation. Significant progress has been made in the mechanistic description of pore formation for the different PFTs families, but in several cases a complete understanding of pore structure remains lacking. PFTs have evolved recognition mechanisms to bind specific receptors that define their host tropism, although this can be remarkably diverse even within the same family. Here we summarise the salient features of PFTs and highlight where additional research is necessary to fully understand the mechanism of pore formation by members of this diverse group of protein toxins.
Topics: Bacteria; Bacterial Toxins; Cell Membrane; Humans; Pore Forming Cytotoxic Proteins; Virulence Factors
PubMed: 35333704
DOI: 10.1099/mic.0.001154 -
Toxins Jun 2023Toxin-antitoxin (TA) systems are widely present in bacterial genomes. They consist of stable toxins and unstable antitoxins that are classified into distinct groups... (Review)
Review
Toxin-antitoxin (TA) systems are widely present in bacterial genomes. They consist of stable toxins and unstable antitoxins that are classified into distinct groups based on their structure and biological activity. TA systems are mostly related to mobile genetic elements and can be easily acquired through horizontal gene transfer. The ubiquity of different homologous and non-homologous TA systems within a single bacterial genome raises questions about their potential cross-interactions. Unspecific cross-talk between toxins and antitoxins of non-cognate modules may unbalance the ratio of the interacting partners and cause an increase in the free toxin level, which can be deleterious to the cell. Moreover, TA systems can be involved in broadly understood molecular networks as transcriptional regulators of other genes' expression or modulators of cellular mRNA stability. In nature, multiple copies of highly similar or identical TA systems are rather infrequent and probably represent a transition stage during evolution to complete insulation or decay of one of them. Nevertheless, several types of cross-interactions have been described in the literature to date. This implies a question of the possibility and consequences of the TA system cross-interactions, especially in the context of the practical application of the TA-based biotechnological and medical strategies, in which such TAs will be used outside their natural context, will be artificially introduced and induced in the new hosts. Thus, in this review, we discuss the prospective challenges of system cross-talks in the safety and effectiveness of TA system usage.
Topics: Bacterial Toxins; Prospective Studies; Toxin-Antitoxin Systems; Bacteria; Antitoxins; Biotechnology; Bacterial Proteins
PubMed: 37368681
DOI: 10.3390/toxins15060380 -
International Journal of Molecular... Nov 2022The huge advances in genomics and molecular biology in the past two decades have made now an exciting time to study bacterial toxins, in particular, the most potent...
The huge advances in genomics and molecular biology in the past two decades have made now an exciting time to study bacterial toxins, in particular, the most potent bacterial toxin known to humankind, botulinum neurotoxins (BoNTs) [...].
Topics: Neurotoxins; Clostridium; Botulinum Toxins; Bacterial Toxins; Genomics
PubMed: 36430554
DOI: 10.3390/ijms232214076 -
Toxins Apr 2018Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the genomic island, was... (Review)
Review
Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the genomic island, was discovered in 2006. Despite many efforts, colibactin has not yet been purified, and its structure remains elusive. Interestingly, the island is found in members of the family (mainly and ) isolated from different origins, including from intestinal microbiota, septicaemia, newborn meningitis, and urinary tract infections. Colibactin-producing bacteria induce chromosomal instability and DNA damage in eukaryotic cells, which leads to senescence of epithelial cells and apoptosis of immune cells. The island is mainly observed in B2 phylogroup strains, which include extra-intestinal pathogenic strains, and are over-represented in biopsies isolated from colorectal cancer. In addition, bacteria increase the number of tumours in diverse colorectal cancer mouse models. Thus, colibactin could have a major impact on human health. In the present review, we will focus on the biological effects of colibactin, the distribution of the island, and summarize what is currently known about its synthesis and its structure.
Topics: Animals; Bacterial Toxins; Genomic Islands; Humans; Mutagens; Peptides; Polyketides
PubMed: 29642622
DOI: 10.3390/toxins10040151 -
FEMS Microbiology Reviews Sep 2023Toxin-antitoxin (TA) systems are entities found in the prokaryotic genomes, with eight reported types. Type II, the best characterized, is comprised of two genes...
Toxin-antitoxin (TA) systems are entities found in the prokaryotic genomes, with eight reported types. Type II, the best characterized, is comprised of two genes organized as an operon. Whereas toxins impair growth, the cognate antitoxin neutralizes its activity. TAs appeared to be involved in plasmid maintenance, persistence, virulence, and defence against bacteriophages. Most Type II toxins target the bacterial translational machinery. They seem to be antecessors of Higher Eukaryotes and Prokaryotes Nucleotide-binding (HEPN) RNases, minimal nucleotidyltransferase domains, or CRISPR-Cas systems. A total of four TAs encoded by Streptococcus pneumoniae, RelBE, YefMYoeB, Phd-Doc, and HicAB, belong to HEPN-RNases. The fifth is represented by PezAT/Epsilon-Zeta. PezT/Zeta toxins phosphorylate the peptidoglycan precursors, thereby blocking cell wall synthesis. We explore the body of knowledge (facts) and hypotheses procured for Type II TAs and analyse the data accumulated on the PezAT family. Bioinformatics analyses showed that homologues of PezT/Zeta toxin are abundantly distributed among 14 bacterial phyla mostly in Proteobacteria (48%), Firmicutes (27%), and Actinobacteria (18%), showing the widespread distribution of this TA. The pezAT locus was found to be mainly chromosomally encoded whereas its homologue, the tripartite omega-epsilon-zeta locus, was found mostly on plasmids. We found several orphan pezT/zeta toxins, unaccompanied by a cognate antitoxin.
Topics: Antitoxins; Bacterial Toxins; Bacteria; Operon; Prokaryotic Cells; Bacterial Proteins
PubMed: 37715317
DOI: 10.1093/femsre/fuad052 -
Toxins Mar 2016Anthrax is a severe, although rather rare, infectious disease that is caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. The infectious form is the... (Review)
Review
Anthrax is a severe, although rather rare, infectious disease that is caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. The infectious form is the spore and the major virulence factors of the bacterium are its poly-γ-D-glutamic acid capsule and the tripartite anthrax toxin. The discovery of the anthrax toxin receptors in the early 2000s has allowed in-depth studies on the mechanisms of anthrax toxin cellular entry and translocation from the endocytic compartment to the cytoplasm. The toxin generally hijacks the endocytic pathway of CMG2 and TEM8, the two anthrax toxin receptors, in order to reach the endosomes. From there, the pore-forming subunit of the toxin inserts into endosomal membranes and enables translocation of the two catalytic subunits. Insertion of the pore-forming unit preferentially occurs in intraluminal vesicles rather than the limiting membrane of the endosome, leading to the translocation of the enzymatic subunits in the lumen of these vesicles. This has important consequences that will be discussed. Ultimately, the toxins reach the cytosol where they act on their respective targets. Target modification has severe consequences on cell behavior, in particular on cells of the immune system, allowing the spread of the bacterium, in severe cases leading to host death. Here we will review the literature on anthrax disease with a focus on the structure of the toxin, how it enters cells and its immunological effects.
Topics: Animals; Antigens, Bacterial; Bacterial Toxins; Endocytosis; Humans; Receptors, Peptide
PubMed: 26978402
DOI: 10.3390/toxins8030069 -
Frontiers in Cellular and Infection... 2021The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have... (Review)
Review
The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have evolved molecular mechanisms to facilitate adaptation to environmental changes within the infected host. Small RNAs (sRNAs) have been implicated as critical regulators of numerous pathways and systems in pathogenic bacteria, including that of bacterial Toxin-Antitoxin (TA) systems. TA systems are typically composed of two factors, a stable toxin, and a labile antitoxin which functions to protect against the potentially deleterious activity of the associated toxin. Of the six classes of bacterial TA systems characterized to date, the toxin component is always a protein. Type I and Type III TA systems are unique in that the antitoxin in these systems is an RNA molecule, whereas the antitoxin in all other TA systems is a protein. Though hotly debated, the involvement of TA systems in bacterial physiology is recognized by several studies, with the Type II TA system being the most extensively studied to date. This review focuses on RNA-regulated TA systems, highlighting the role of Type I and Type III TA systems in several pathogenic bacteria.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; RNA; Toxin-Antitoxin Systems
PubMed: 34084755
DOI: 10.3389/fcimb.2021.661026 -
Molecular Cell Jun 2018Bacterial toxin-antitoxin (TA) modules are abundant genetic elements that encode a toxin protein capable of inhibiting cell growth and an antitoxin that counteracts the... (Review)
Review
Bacterial toxin-antitoxin (TA) modules are abundant genetic elements that encode a toxin protein capable of inhibiting cell growth and an antitoxin that counteracts the toxin. The majority of toxins are enzymes that interfere with translation or DNA replication, but a wide variety of molecular activities and cellular targets have been described. Antitoxins are proteins or RNAs that often control their cognate toxins through direct interactions and, in conjunction with other signaling elements, through transcriptional and translational regulation of TA module expression. Three major biological functions of TA modules have been discovered, post-segregational killing ("plasmid addiction"), abortive infection (bacteriophage immunity through altruistic suicide), and persister formation (antibiotic tolerance through dormancy). In this review, we summarize the current state of the field and highlight how multiple levels of regulation shape the conditions of toxin activation to achieve the different biological functions of TA modules.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Drug Resistance, Bacterial; Evolution, Molecular; Gene Expression Regulation, Bacterial; Immunity, Innate; Microbial Viability; Models, Molecular; Nucleic Acid Conformation; Protein Conformation; RNA Processing, Post-Transcriptional; RNA, Bacterial; Structure-Activity Relationship; Transcription, Genetic
PubMed: 29398446
DOI: 10.1016/j.molcel.2018.01.003 -
Current Opinion in Microbiology Feb 2022Clostridioides difficile produces toxins TcdA and TcdB during infection. Since the severity of the illness is directly correlated with the level of toxins produced,... (Review)
Review
Clostridioides difficile produces toxins TcdA and TcdB during infection. Since the severity of the illness is directly correlated with the level of toxins produced, researchers have long been interested in the regulation mechanisms of toxin production. The advent of new genetics and mutagenesis technologies in C. difficile has allowed a slew of new investigations in the last decade, which considerably improved our understanding of this crucial regulatory network. The current body of work shows that the toxin regulatory network overlaps with the regulatory networks of sporulation, motility, and key metabolic pathways. This implies that toxin production is a complicated process initiated by bacteria in response to numerous host factors during infection. We summarize the existing knowledge about the toxin gene regulatory network here.
Topics: Bacterial Proteins; Bacterial Toxins; Clostridioides difficile; Enterotoxins
PubMed: 34781095
DOI: 10.1016/j.mib.2021.10.018