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The Oncologist Feb 2015Immunotoxins are a novel class of antibody-conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody-based... (Review)
Review
Immunotoxins are a novel class of antibody-conjugated therapeutics currently in clinical development for a variety of malignancies. They consist of an antibody-based targeting domain fused to a bacterial toxin payload for cell killing. Immunotoxins kill cells by inhibiting protein synthesis, a unique mechanism of action that is toxic to both dividing and nondividing cells. Recent advances in the design and administration of immunotoxins are overcoming historical challenges in the field, leading to renewed interest in these therapeutics.
Topics: Bacterial Toxins; Humans; Immunotoxins; Neoplasms; Protein Biosynthesis
PubMed: 25561510
DOI: 10.1634/theoncologist.2014-0358 -
Oncotarget Aug 2015
Topics: Bacterial Toxins; Humans; Vibrio vulnificus; rap1 GTP-Binding Proteins; ras Proteins
PubMed: 26300052
DOI: 10.18632/oncotarget.5113 -
Biotechnology Advances Oct 2022Glycan-recognizing toxins play a significant role in the etiology of many diseases afflicting humanity. The carbohydrate recognition domains of these toxins play... (Review)
Review
Glycan-recognizing toxins play a significant role in the etiology of many diseases afflicting humanity. The carbohydrate recognition domains of these toxins play essential roles in the virulence of many microbial organisms with multiple modes of action, from promoting pore formation to facilitating the entry of toxic enzymatic subunits into the host cell. Carbohydrate-binding domains with an affinity for specific glycan-based receptors can also be exploited for various applications, including detecting glycobiomarkers, as drug delivery systems, and new generation biopharmaceutical products and devices (e.g. glycoselective capture of tumor-derived exosomes). Therefore, understanding how to efficiently express and purify recombinant toxins and their carbohydrate-binding domains can enable opportunities for the formulation of innovative biopharmaceuticals that can improve human health. Here, we provide an overview of carbohydrate-binding toxins in the context of biotechnological innovation. We review 1) structural characteristics concerning the toxins' mode of action; 2) applications and therapeutic design with a particular emphasis on exploiting carbohydrate-binding toxins for production of anti-tumor biopharmaceuticals; discuss 3) possible ways to manufacture those molecules at a bioreactor scale using microbial expression systems, and 4) their purification using their affinity for glycans.
Topics: Bacterial Toxins; Biological Products; Carbohydrates; Humans; Polysaccharides
PubMed: 35398203
DOI: 10.1016/j.biotechadv.2022.107951 -
PLoS Genetics Oct 2017Host-targeting type IV secretion systems (T4SS) evolved from conjugative T4SS machineries that mediate interbacterial plasmid transfer. However, the origins of effectors...
Host-targeting type IV secretion systems (T4SS) evolved from conjugative T4SS machineries that mediate interbacterial plasmid transfer. However, the origins of effectors secreted by these virulence devices have remained largely elusive. Previous work showed that some effectors exhibit homology to toxins of bacterial toxin-antitoxin modules, but the evolutionary trajectories underlying these ties had not been resolved. We previously reported that FicT toxins of FicTA toxin-antitoxin modules disrupt cellular DNA topology via their enzymatic FIC (filamentation induced by cAMP) domain. Intriguingly, the FIC domain of the FicT toxin VbhT of Bartonella schoenbuchensis is fused to a type IV secretion signal-the BID (Bep intracellular delivery) domain-similar to the Bartonella effector proteins (Beps) that are secreted into eukaryotic host cells via the host-targeting VirB T4SS. In this study, we show that the VbhT toxin is an interbacterial effector protein secreted via the conjugative Vbh T4SS that is closely related to the VirB T4SS and encoded by plasmid pVbh of B. schoenbuchensis. We therefore propose that the Vbh T4SS together with its effector VbhT represent an evolutionary missing link on a path that leads from a regular conjugation system and FicTA toxin-antitoxin modules to the VirB T4SS and the Beps. Intriguingly, phylogenetic analyses revealed that the fusion of FIC and BID domains has probably occurred independently in VbhT and the common ancestor of the Beps, suggesting parallel evolutionary paths. Moreover, several other examples of TA module toxins that are bona fide substrates of conjugative T4SS indicate that their recruitment as interbacterial effectors is prevalent and serves yet unknown biological functions in the context of bacterial conjugation. We propose that the adaptation for interbacterial transfer favors the exaptation of FicT and other TA module toxins as inter-kingdom effectors and may thus constitute an important stepping stone in the evolution of host-targeted effector proteins.
Topics: Amino Acid Sequence; Antitoxins; Bacterial Proteins; Bacterial Secretion Systems; Bacterial Toxins; Bartonella; Bartonella Infections; Conjugation, Genetic; Gene Expression Regulation, Bacterial; Host-Pathogen Interactions; Plasmids; Sequence Homology; Virulence
PubMed: 29073136
DOI: 10.1371/journal.pgen.1007077 -
Nature Mar 2022Colibactin is a chemically unstable small-molecule genotoxin that is produced by several different bacteria, including members of the human gut microbiome. Although the...
Colibactin is a chemically unstable small-molecule genotoxin that is produced by several different bacteria, including members of the human gut microbiome. Although the biological activity of colibactin has been extensively investigated in mammalian systems, little is known about its effects on other microorganisms. Here we show that colibactin targets bacteria that contain prophages, and induces lytic development through the bacterial SOS response. DNA, added exogenously, protects bacteria from colibactin, as does expressing a colibactin resistance protein (ClbS) in non-colibactin-producing cells. The prophage-inducing effects that we observe apply broadly across different phage-bacteria systems and in complex communities. Finally, we identify bacteria that have colibactin resistance genes but lack colibactin biosynthetic genes. Many of these bacteria are infected with predicted prophages, and we show that the expression of their ClbS homologues provides immunity from colibactin-triggered induction. Our study reveals a mechanism by which colibactin production could affect microbiomes and highlights a role for microbial natural products in influencing population-level events such as phage outbreaks.
Topics: Bacteria; Bacterial Toxins; Bacteriolysis; Microbial Interactions; Peptides; Polyketides; Prophages; SOS Response, Genetics; Virus Activation
PubMed: 35197633
DOI: 10.1038/s41586-022-04444-3 -
The FEBS Journal Dec 2011Epsilon toxin (ETX) is produced by strains of Clostridium perfringens classified as type B or type D. ETX belongs to the heptameric β-pore-forming toxins including... (Review)
Review
Epsilon toxin (ETX) is produced by strains of Clostridium perfringens classified as type B or type D. ETX belongs to the heptameric β-pore-forming toxins including aerolysin and Clostridium septicum alpha toxin, which are characterized by the formation of a pore through the plasma membrane of eukaryotic cells consisting in a β-barrel of 14 amphipatic β strands. By contrast to aerolysin and C. septicum alpha toxin, ETX is a much more potent toxin and is responsible for enterotoxemia in animals, mainly sheep. ETX induces perivascular edema in various tissues and accumulates in particular in the kidneys and brain, where it causes edema and necrotic lesions. ETX is able to pass through the blood-brain barrier and stimulate the release of glutamate, which accounts for the symptoms of nervous excitation observed in animal enterotoxemia. At the cellular level, ETX causes rapid swelling followed by cell death involving necrosis. The precise mode of action of ETX remains to be determined. ETX is a powerful toxin, however, it also represents a unique tool with which to vehicle drugs into the central nervous system or target glutamatergic neurons.
Topics: Animals; Bacterial Toxins; Blood-Brain Barrier; Brain; Cell Death; Clostridium perfringens; Enterotoxemia; Humans; Kidney; Necrosis
PubMed: 21535407
DOI: 10.1111/j.1742-4658.2011.08145.x -
Toxins Feb 2016Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and... (Review)
Review
Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and the other, its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin, causing activation of the toxin, leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell, including acting as mediators of programmed cell death, the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications, which are the subject of this review. Here, we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes, for the containment of genetically modified organisms, and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies.
Topics: Animals; Antitoxins; Bacterial Toxins; Eukaryotic Cells; Genetic Engineering; Genetic Therapy; Humans; Yeasts
PubMed: 26907343
DOI: 10.3390/toxins8020049 -
MBio Feb 2021Bacterial cells utilize toxin-antitoxin systems to inhibit self-reproduction, while maintaining viability, when faced with environmental challenges. The activation of...
Bacterial cells utilize toxin-antitoxin systems to inhibit self-reproduction, while maintaining viability, when faced with environmental challenges. The activation of the toxin is often coupled to the induction of cellular response pathways, such as the stringent response, in response to multiple stress conditions. Under these conditions, the cell enters a quiescent state referred to as dormancy or persistence. How toxin activation triggers persistence and induces a systemic stress response in the alphaproteobacteria remains unclear. Here, we report that in , a -encoded bacterial toxin contributes to bacterial persistence by manipulating intracellular amino acid balance. HipA2 is a serine/threonine kinase that deactivates tryptophanyl-tRNA synthetase by phosphorylation, leading to stalled protein synthesis and the accumulation of free tryptophan. An increased level of tryptophan allosterically activates the adenylyltransferase activity of GlnE that, in turn, deactivates glutamine synthetase GlnA by adenylylation. The inactivation of GlnA promotes the deprivation of glutamine in the cell, which triggers a stringent response. By screening 69 stress conditions, we find that HipBA2 responds to multiple stress signals through the proteolysis of HipB2 antitoxin by the Lon protease and the release of active HipA2 kinase, revealing a molecular mechanism that allows disparate stress conditions to be sensed and funneled into a single response pathway. To overcome various environmental challenges, bacterial cells can enter a physiologically quiescent state, known as dormancy or persistence, which balances growth and viability. In this study, we report a new mechanism by which a toxin-antitoxin system responds to harsh environmental conditions or nutrient deprivation by orchestrating a dormant state while preserving viability. The -encoded kinase functions as a toxin in , inducing bacterial persistence by disturbing the intracellular tryptophan-glutamine balance. A nitrogen regulatory circuit can be regulated by the intracellular level of tryptophan, which mimics the allosteric role of glutamine in this feedback loop. The HipBA2 module senses different types of stress conditions by increasing the intracellular level of tryptophan, which in turn breaks the tryptophan-glutamine balance and induces glutamine deprivation. Our results reveal a molecular mechanism that allows disparate environmental challenges to converge on a common pathway that results in a dormant state.
Topics: Amino Acids; Bacterial Proteins; Bacterial Toxins; Caulobacter; Cytoplasm; Gene Expression Regulation, Bacterial; Glutamine; Protein Biosynthesis; Toxin-Antitoxin Systems; Tryptophan
PubMed: 33622732
DOI: 10.1128/mBio.03020-20 -
Current Genetics Feb 2019Autoregulation is the direct modulation of gene expression by the product of the corresponding gene. Autoregulation of bacterial gene expression has been mostly studied... (Review)
Review
Autoregulation is the direct modulation of gene expression by the product of the corresponding gene. Autoregulation of bacterial gene expression has been mostly studied at the transcriptional level, when a protein acts as the cognate transcriptional repressor. A recent study investigating dynamics of the bacterial toxin-antitoxin MazEF system has shown how autoregulation at both the transcriptional and post-transcriptional levels affects the heterogeneity of Escherichia coli populations. Toxin-antitoxin systems hold a crucial but still elusive part in bacterial response to stress. This perspective highlights how these modules can also serve as a great model system for investigating basic concepts in gene regulation. However, as the genomic background and environmental conditions substantially influence toxin activation, it is important to study (auto)regulation of toxin-antitoxin systems in well-defined setups as well as in conditions that resemble the environmental niche.
Topics: Bacteria; Bacterial Proteins; Bacterial Toxins; DNA-Binding Proteins; Endoribonucleases; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Homeostasis; Toxin-Antitoxin Systems
PubMed: 30132188
DOI: 10.1007/s00294-018-0879-8 -
Journal of Applied Microbiology Mar 2018Infectious diseases are among the common leading causes of morbidity and mortality worldwide. Associated with the emergence of new infectious diseases, the increasing... (Review)
Review
Infectious diseases are among the common leading causes of morbidity and mortality worldwide. Associated with the emergence of new infectious diseases, the increasing number of antimicrobial-resistant isolates presents a serious threat to public health and hospitalized patients. A microbial pathogen may elicit several host responses and use a variety of mechanisms to evade host defences. These methods and mechanisms include capsule, lipopolysaccharides or cell wall components, adhesions and toxins. Toxins inhibit phagocytosis, cause septic shock and host cell damages by binding to host surface receptors and invasion. Bacterial and fungal pathogens are able to apply many different toxin-dependent mechanisms to disturb signalling pathways and the structural integrity of host cells for establishing and maintaining infections Initial techniques for analysis of bacterial toxins were based on in vivo or in vitro assessments. There is a permanent demand for appropriate detection methods which are affordable, practical, careful, rapid, sensitive, efficient and economical. Aptamers are DNA or RNA oligonucleotides that are selected by systematic evolution of ligands using exponential enrichment (SELEX) methods and can be applied in diagnostic applications. This review provides an overview of aptamer-based methods as a novel approach for detecting toxins in bacterial and fungal pathogens.
Topics: Aptamers, Nucleotide; Bacterial Toxins; Enzyme-Linked Immunosorbent Assay; Ligands; Mycotoxins; SELEX Aptamer Technique
PubMed: 29171901
DOI: 10.1111/jam.13650