-
Trends in Microbiology Jun 2012Toxin-antitoxin (TA) systems are unique modules that effect plasmid stabilization via post-segregational killing of the bacterial host. The genes encoding TA systems... (Review)
Review
Toxin-antitoxin (TA) systems are unique modules that effect plasmid stabilization via post-segregational killing of the bacterial host. The genes encoding TA systems also exist on bacterial chromosomes, and it has been speculated that these are involved in a variety of cellular processes. Interest in TA systems has increased dramatically over the past 5 years as the ubiquitous nature of TA genes on bacterial genomes has been revealed. The exploitation of TA systems as an antibacterial strategy via artificial activation of the toxin has been proposed and has considerable potential; however, efforts in this area remain in the early stages and several major questions remain. This review investigates the tractability of targeting TA systems to kill bacteria, including fundamental requirements for success, recent advances, and challenges associated with artificial toxin activation.
Topics: Bacterial Infections; Bacterial Toxins; Humans; Microbial Viability; Plasmids; Transcriptional Activation
PubMed: 22445361
DOI: 10.1016/j.tim.2012.02.005 -
Microbiological Reviews Dec 1991Alpha-toxin, the major cytotoxic agent elaborated by Staphylococcus aureus, was the first bacterial exotoxin to be identified as a pore former. The protein is secreted... (Review)
Review
Alpha-toxin, the major cytotoxic agent elaborated by Staphylococcus aureus, was the first bacterial exotoxin to be identified as a pore former. The protein is secreted as a single-chain, water-soluble molecule of Mr 33,000. At low concentrations (less than 100 nM), the toxin binds to as yet unidentified, high-affinity acceptor sites that have been detected on a variety of cells including rabbit erythrocytes, human platelets, monocytes and endothelial cells. At high concentrations, the toxin additionally binds via nonspecific absorption to lipid bilayers; it can thus damage both cells lacking significant numbers of the acceptor and protein-free artificial lipid bilayers. Membrane damage occurs in both cases after membrane-bound toxin molecules collide via lateral diffusion to form ring-structured hexamers. The latter insert spontaneously into the lipid bilayer to form discrete transmembrane pores of effective diameter 1 to 2 nm. A hypothetical model is advanced in which the pore is lined by amphiphilic beta-sheets, one surface of which interacts with lipids whereas the other repels apolar membrane constitutents to force open an aqueous passage. The detrimental effects of alpha-toxin are due not only to the death of susceptible targets, but also to the presence of secondary cellular reactions that can be triggered via Ca2+ influx through the pores. Well-studied phenomena include the stimulation of arachidonic acid metabolism, triggering of granule exocytosis, and contractile dysfunction. Such processes cause profound long-range disturbances such as development of pulmonary edema and promotion of blood coagulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Bacterial Toxins; Cell Membrane; Cell Membrane Permeability; Hemolysin Proteins; Humans; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 1779933
DOI: 10.1128/mr.55.4.733-751.1991 -
Toxins Jun 2013Staphylococcus aureus secretes a number of host-injurious toxins, among the most prominent of which is the small β-barrel pore-forming toxin α-hemolysin. Initially... (Review)
Review
Staphylococcus aureus secretes a number of host-injurious toxins, among the most prominent of which is the small β-barrel pore-forming toxin α-hemolysin. Initially named based on its properties as a red blood cell lytic toxin, early studies suggested a far greater complexity of α-hemolysin action as nucleated cells also exhibited distinct responses to intoxication. The hemolysin, most aptly referred to as α-toxin based on its broad range of cellular specificity, has long been recognized as an important cause of injury in the context of both skin necrosis and lethal infection. The recent identification of ADAM10 as a cellular receptor for α-toxin has provided keen insight on the biology of toxin action during disease pathogenesis, demonstrating the molecular mechanisms by which the toxin causes tissue barrier disruption at host interfaces lined by epithelial or endothelial cells. This review highlights both the historical studies that laid the groundwork for nearly a century of research on α-toxin and key findings on the structural and functional biology of the toxin, in addition to discussing emerging observations that have significantly expanded our understanding of this toxin in S. aureus disease. The identification of ADAM10 as a proteinaceous receptor for the toxin not only provides a greater appreciation of truths uncovered by many historic studies, but now affords the opportunity to more extensively probe and understand the role of α-toxin in modulation of the complex interaction of S. aureus with its human host.
Topics: Animals; Antibodies, Bacterial; Bacterial Toxins; Hemolysin Proteins; Humans; Protein Conformation; Staphylococcal Infections
PubMed: 23888516
DOI: 10.3390/toxins5061140 -
International Journal of Molecular... May 2018Cytotoxic necrotizing factor 1 (CNF1) is a bacterial protein toxin primarily expressed by pathogenic strains, causing extraintestinal infections. The toxin is believed...
Cytotoxic necrotizing factor 1 (CNF1) is a bacterial protein toxin primarily expressed by pathogenic strains, causing extraintestinal infections. The toxin is believed to enhance the invasiveness of by modulating the activity of Rho GTPases in host cells, but it has interestingly also been shown to promote inflammation, stimulate host immunity and function as a potent immunoadjuvant. The mechanisms underlying the immunostimulatory properties of CNF1 are, however, poorly characterized, and little is known about the direct effects of the toxin on immune cells. Here, we show that CNF1 induces expression of maturation markers on human immature monocyte-derived dendritic cells (moDCs) without compromising cell viability. Consistent with the phenotypic maturation, CNF1 further triggered secretion of proinflammatory cytokines and increased the capacity of moDCs to stimulate proliferation of allogenic naïve CD4+ T cells. A catalytically inactive form of the toxin did not induce moDC maturation, indicating that the enzymatic activity of CNF1 triggers immature moDCs to undergo phenotypic and functional maturation. As the maturation of dendritic cells plays a central role in initiating inflammation and activating the adaptive immune response, the present findings shed new light on the immunostimulatory properties of CNF1 and may explain why the toxin functions as an immunoadjuvant.
Topics: Adjuvants, Immunologic; Bacterial Toxins; Cell Survival; Dendritic Cells; Escherichia coli; Escherichia coli Proteins; Humans; Inflammation; Monocytes; rho GTP-Binding Proteins
PubMed: 29738516
DOI: 10.3390/ijms19051408 -
Biochimica Et Biophysica Acta.... Nov 2021Protective antigen channel is the central component of the deadly anthrax exotoxin responsible for binding and delivery of the toxin's enzymatic lethal and edema factor... (Review)
Review
Protective antigen channel is the central component of the deadly anthrax exotoxin responsible for binding and delivery of the toxin's enzymatic lethal and edema factor components into the cytosol. The channel, which is more than three times longer than the lipid bilayer membrane thickness and has a 6-Å limiting diameter, is believed to provide a sophisticated unfoldase and translocase machinery for the foreign protein transport into the host cell cytosol. The tripartite toxin can be reengineered, one component at a time or collectively, to adapt it for the targeted cancer therapeutic treatments. In this review, we focus on the biophysical studies of the protective antigen channel-forming activity, small ion transport properties, enzymatic factor translocation, and blockage comparing it with the related clostridial binary toxin channels. We address issues linked to the anthrax toxin channel structural dynamics and lipid dependence, which are yet to become generally recognized as parts of the toxin translocation machinery.
Topics: Antigens, Bacterial; Bacterial Toxins; Hydrogen-Ion Concentration; Lipid Bilayers; Protein Conformation; Protein Transport
PubMed: 34332985
DOI: 10.1016/j.bbamem.2021.183715 -
Trends in Microbiology Nov 2019Most bacteria use toxins to exclude competitors. As the synthesis and delivery of these molecules entail considerable costs for the producers, their expression is... (Review)
Review
Most bacteria use toxins to exclude competitors. As the synthesis and delivery of these molecules entail considerable costs for the producers, their expression is tightly regulated, often by molecular systems detecting physiological stresses or environment-specific cues. However, the ecological connection between such systems and competitive behaviors is not always clear. Here, we review the regulation of antibacterial toxins and propose a conceptual framework organizing the decision-making processes controlling toxin production. As bacteria are unable to precisely identify their competitors, we argue that toxin regulation primarily responds to cues directly or indirectly associated with the presence of competing strains. The density and fitness of the producing population also play a role in the decision-making process. Overall, we contend that optimal toxin production strategies involve monitoring of both self and foe.
Topics: Bacterial Physiological Phenomena; Bacterial Toxins; Microbial Interactions
PubMed: 31231027
DOI: 10.1016/j.tim.2019.05.009 -
Nucleic Acids Research Feb 2021Antibiotic resistance is a serious problem which may be caused by bacterial dormancy. It has been suggested that bacterial toxin-antitoxin systems induce dormancy. We...
Antibiotic resistance is a serious problem which may be caused by bacterial dormancy. It has been suggested that bacterial toxin-antitoxin systems induce dormancy. We analyzed the genome-wide role of Staphylococcus aureus endoribonuclease toxin MazF using RNA-Seq, Ribo-Seq and quantitative proteomics. We characterized changes in transcriptome, translatome and proteome caused by MazF, and proposed that MazF decreases translation directly by cleaving mRNAs, and indirectly, by decreasing translation factors and by promoting ribosome hibernation. Important pathways affected during the early stage of MazF induction were identified: MazF increases cell wall thickness and decreases cell division; MazF activates SsrA-system which rescues stalled ribosomes, appearing as a result of MazF mRNA cleavage. These pathways may be promising targets for new antibacterial drugs that prevent bacteria dormancy. Finally, we described the overall impact of MazF on S. aureus cell physiology, and propose one of the mechanisms by which MazF might regulate cellular changes leading to dormancy.
Topics: Bacterial Toxins; Cell Division; Cell Wall; Endoribonucleases; Protein Biosynthesis; Proteome; Staphylococcus aureus; Transcriptome
PubMed: 33544858
DOI: 10.1093/nar/gkaa1292 -
Frontiers in Bioscience (Landmark... Jan 2009Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. After entering the body, the spores germinate into bacteria and secrete a... (Review)
Review
Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. After entering the body, the spores germinate into bacteria and secrete a toxin that causes local edema and, in systemic infections, cardiovascular collapse and death. The toxin is a tripartite polypeptide, consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF), which have key roles in the bacterial pathogenesis and disease progression. PA facilitates transfer of LF and EF to the cytosol. Lethal toxin is a zinc metalloproteinase, which has the capacity to inactivate mitogen-activated protein (MAP) kinase kinase (MEK) and stimulates the release of sepsis-related cytokines tumor necrosis factor-alpha and interleukin-1beta. Edema factor is a calmodulin (CaM)-dependent adenylate cyclase, which increases levels of cyclic AMP, causing impaired neutrophil function and disruption of water balance that ultimately results in massive tissue edema. Together, the toxins effectively inhibit host innate and adaptive immune responses, allowing the bacteria to grow unrestrained and overwhelming any resistance. Clinically, inhalational anthrax presents in a biphasic pattern with initial nonspecific "flu-like" symptoms nausea and vomiting 1 to 4 days after exposure, followed by severe illness with dyspnea, high fever and circulatory shock. The latter symptoms represent a terminal stage and treatment is often ineffective when started at that time. Key indicators of early anthrax cardiovascular-related pathogenesis include mediastinal widening in association with pleural effusion and edema. In this review, we describe the current understanding of anthrax toxins on cellular function in the context of cardiovascular function and discuss potential therapeutic strategies.
Topics: Anthrax; Antigens, Bacterial; Bacterial Toxins; Cardiovascular System; Humans
PubMed: 19273204
DOI: 10.2741/3382 -
Cell Reports Feb 2024The G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD, are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major...
The G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD, are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major virulence factor responsible for pathogenesis associated with Clostridioides difficile infection. We employ a live-cell assay examining the affinity between full-length FZDs and TcdB. Moreover, we present cryoelectron microscopy structures of TcdB alone and in complex with full-length FZD, which reveal that large structural rearrangements of the combined repetitive polypeptide domain are required for interaction with FZDs and other TcdB receptors, constituting a first step for receptor recognition. Furthermore, we show that bezlotoxumab, an FDA-approved monoclonal antibody to treat Clostridioides difficile infection, favors the apo-TcdB structure and thus disrupts binding with FZD. The dynamic transition between the two conformations of TcdB also governs the stability of the pore-forming region. Thus, our work provides structural and functional insight into how conformational dynamics of TcdB determine receptor binding.
Topics: Humans; Bacterial Toxins; Clostridioides difficile; Cryoelectron Microscopy; Clostridium Infections; Boron Compounds
PubMed: 38308843
DOI: 10.1016/j.celrep.2024.113727 -
Nature Communications Nov 2016Bacterial toxin-antitoxin (TA) systems, in which a labile antitoxin binds and inhibits the toxin, can promote adaptation and persistence by modulating bacterial growth...
Bacterial toxin-antitoxin (TA) systems, in which a labile antitoxin binds and inhibits the toxin, can promote adaptation and persistence by modulating bacterial growth in response to stress. Some atypical TA systems, known as tripartite toxin-antitoxin-chaperone (TAC) modules, include a molecular chaperone that facilitates folding and protects the antitoxin from degradation. Here we use a TAC module from Mycobacterium tuberculosis as a model to investigate the molecular mechanisms by which classical TAs can become 'chaperone-addicted'. The chaperone specifically binds the antitoxin at a short carboxy-terminal sequence (chaperone addiction sequence, ChAD) that is not present in chaperone-independent antitoxins. In the absence of chaperone, the ChAD sequence destabilizes the antitoxin, thus preventing toxin inhibition. Chaperone-ChAD pairs can be transferred to classical TA systems or to unrelated proteins and render them chaperone-dependent. This mechanism might be used to optimize the expression and folding of heterologous proteins in bacterial hosts for biotechnological or medical purposes.
Topics: Bacterial Proteins; Bacterial Toxins; Molecular Chaperones; Mycobacterium tuberculosis; Protein Folding; Recombinant Proteins; Toxin-Antitoxin Systems
PubMed: 27827369
DOI: 10.1038/ncomms13339