Pathogenicity and virulence of Clostridium botulinum

Virulence, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 8, 2023

Clostridium botulinum, a polyphyletic Gram-positive taxon of bacteria, is classified purely by their ability to produce botulinum neurotoxin (BoNT). BoNT the primary virulence factor and causative agent botulism. A potentially fatal disease, botulism classically characterized symmetrical descending flaccid paralysis, which left untreated can lead respiratory failure death. Botulism cases are into three main forms dependent on nature intoxication; foodborne, wound infant. The BoNT, regarded as most potent biological substance known, zinc metalloprotease that specifically cleaves SNARE proteins at neuromuscular junctions, preventing exocytosis neurotransmitters, leading muscle paralysis. now used treat numerous medical conditions caused overactive or spastic muscles extensively in cosmetic industry due its high specificity exceedingly small doses needed exert long-lasting pharmacological effects. Additionally, form endospores critical pathogenicity bacteria. Disease transmission often facilitated via metabolically dormant spores highly resistant environment stresses, allowing persistence unfavourable conditions. Infant infections initiated upon germination producing vegetative cells, whereas foodborne attributed ingestion preformed BoNT. C. saprophytic bacterium, thought have evolved establish source nutrients killing host.

Language: Английский

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Overview of Bacterial Protein Toxins from Pathogenic Bacteria: Mode of Action and Insights into Evolution

Toxins, Journal Year: 2024, Volume and Issue: 16(4), P. 182 - 182

Published: April 8, 2024

Bacterial protein toxins are secreted by certain bacteria and responsible for mild to severe diseases in humans animals. They among the most potent molecules known, which active at very low concentrations. exhibit a wide diversity based on size, structure, mode of action. Upon recognition cell surface receptor (protein, glycoprotein, glycolipid), they either (signal transduction, membrane damage pore formation, or hydrolysis compound(s)) intracellularly. Various bacterial have ability enter cells, often using an endocytosis mechanism, deliver effector domain into cytosol, where it interacts with intracellular target(s). According nature target(s) type modification, various cellular effects induced (cell death, homeostasis cytoskeleton alteration, blockade exocytosis, etc.). The modes action illustrated representative examples. Insights toxin evolution discussed.

Language: Английский

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The impact of orphan histidine kinases and phosphotransfer proteins on the regulation of clostridial sporulation initiation

mBio, Journal Year: 2024, Volume and Issue: 15(4)

Published: March 17, 2024

Sporulation is an important feature of the clostridial life cycle, facilitating survival these bacteria in harsh environments, contributing to disease transmission for pathogenic species, and sharing common early steps that are also involved regulating industrially solvent production by some non-pathogenic species. Initial genomics studies suggested Clostridia lack classical phosphorelay phosphorylates Spo0A initiates sporulation Bacillus, leading hypothesis universally begins when phosphorylated orphan histidine kinases (OHKs). However, components Bacillus were recently identified Clostridia. Similar have not yet been found or solventogenic industrial importance. For those lacking a phosphorelay, involvement OHKs initiation has received support from genetic demonstrating several apparent their sporulation. In addition, directly phosphorylate vitro. Interestingly, there considerable protein domain diversity among sporulation-associated Further adding emergent complexity Clostridia, candidate OHK phosphotransfer proteins candidates shown function as phosphatases reduce The mounting evidence indicates no single pathway explains all supports need further study fully understand unexpected biologically fascinating mechanistic this process medically bacteria.

Language: Английский

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SNARE proteins: Core engines of membrane fusion in cancer

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: unknown, P. 189148 - 189148

Published: July 1, 2024

Language: Английский

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Probing the properties of PTEN specific botulinum toxin type E mutants

Journal of Neural Transmission, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Abstract Botulinum neurotoxins (BoNT) are established biopharmaceuticals for neuromuscular and secretory conditions based on their ability to block neurotransmitter release from neurons by proteolyzing specific soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Recently, a mutant catalytic domain of serotype E (LC/E) exhibiting 16 mutations was reported cleave the phosphatase tensin homolog (PTEN). This molecule represents an attractive new target in as several reports support PTEN knockdown strategy stimulate axonal regeneration after injury. Though this LC/E shown primary through lentivirus-based expression, its expression functionality mutated full-length BoNT/E have not been studied. Hence, we assembled stepwise bacterial plasmid purified multiple mutants LC/E. Biochemical characterization showed that 16-fold did exhibit detectable activity toward SNAP-25 up 10 µM final concentration while it displayed EC 50 approximately 200 nM PTEN, exceeding 1000-fold LC/E-wt native substrate SNAP-25. Unexpectedly, full length provide protein, possibly due interference interaction between LC translocation domain. Reversion individual revealed E159L S162Q substitutions, critical redirecting main culprits solubility issue. To overcome problem, applied methodology proved successful years ago, harnessing proteolytically inactive variant BoNT type D (BoNT/Di) neurospecific delivery system cargo The fusion LCE-16x-BoNT/Di could be produced sufficient yields. Activity tests using rat cerebellar granule BoNT/E-like LC/E-wt-BoNT/Di, but no PTEN-directed LC/E-16x-BoNT/Di.

Language: Английский

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A novel single-domain antibody obtained from immune Bactrian camels against botulinum toxin type A using SPR-based screening method

Heliyon, Journal Year: 2025, Volume and Issue: 11(4), P. e42616 - e42616

Published: Feb. 1, 2025

Botulinum neurotoxin (BoNT) is a highly lethal toxin produced by the anaerobic bacterium Clostridium botulinum, which leads to nerve paralysis following poisoning. At present, there no specific drug officially approved. Antibodies, particularly single-domain antibodies, represent safe and effective candidates for drugs against BoNT. In this study, receptor-binding domain of botulinum (BoNT/AHCC) was utilized immunize Bactrian camels, resulting in generation nanobody phage library. From library, high-affinity binding antibody, designated A1, neutralizing named HM, were successfully obtained through SPR-based screening. The affinity constant HM 1.08E-11 M. Results from computer simulations indicate that binds at same site as SV2C. Furthermore, experimental findings demonstrate exhibits significant blocking activity both vitro level cellular level. mouse toxicity experiments, has been shown offer protection 20 LD50 dose BoNT/A. Consequently, mitigates poisoning mice obstructing AHCC

Language: Английский

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Biotechnological and Therapeutic Applications of Bacterial Toxins

Published: Jan. 1, 2025

Language: Английский

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Regulatory Networks Controlling Neurotoxin Synthesis in Clostridium botulinum and Clostridium tetani

Toxins, Journal Year: 2022, Volume and Issue: 14(6), P. 364 - 364

Published: May 24, 2022

Clostridium botulinum and tetani are Gram-positive, spore-forming, anaerobic bacteria that produce the most potent neurotoxins, toxin (BoNT) tetanus (TeNT), responsible for flaccid spastic paralysis, respectively. The main habitat of these toxigenic is environment (soil, sediments, cadavers, decayed plants, intestinal content healthy carrier animals). C. can grow BoNT in food, leading to food-borne botulism, some circumstances, colonize tract induce infant botulism or adult toxemia botulism. More rarely, colonizes wounds, whereas always a result wound contamination by tetani. synthesis neurotoxins strictly regulated complex regulatory networks. highest levels produced at end exponential growth early stationary phase. Both microorganisms, except E, share an alternative sigma factor, BotR TetR, respectively, genes which located upstream neurotoxin genes. These factors essential gene expression. also two-component system (TCS) negatively regulates synthesis, but each microorganism uses additional distinct sets TCSs. Neurotoxin interlocked with general metabolism, CodY, master regulator metabolism Gram-positive bacteria, involved both clostridial species. environmental nutritional controlling still poorly understood. transition from amino acid peptide seems be important factor. Moreover, small non-coding RNA tetani, quorum-sensing systems possibly control synthesis. However, species use pathways; this reflects adaptation different ecological niches.

Language: Английский

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Comparative analysis of antigenic strength and in vivo serum antibodies concentration of tetanus toxoid vaccine adsorbed in Pakistan

Saudi Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 29(8), P. 103337 - 103337

Published: June 7, 2022

Language: Английский

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Characterization of Serotype CD Mosaic Botulinum Neurotoxin in Comparison with Serotype C and A

Toxins, Journal Year: 2023, Volume and Issue: 15(2), P. 123 - 123

Published: Feb. 3, 2023

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, cleaves proteins involved in neurotransmitter release, thereby triggering flaccid paralyses, which are responsible for botulism. BoNT is classified into seven serotypes (BoNT/A-G); BoNT/A and BoNT/B used as medical therapeutics anti-wrinkle reagents. In this study, we investigated the efficacy of BoNT/CD, a mosaic toxin BoNT/C BoNT/D, to assess its potential therapeutic alternative BoNT/A. cultured neuron assay, BoNT/CD cleaved syntaxin SNAP-25 with higher than Intramuscularly administrated induced dose-dependent muscle paralysis, paralysis lasted ~21 days mouse digit abduction score assay (BoNT/A-induced ~30 days). failed induce local without systemic toxicity. Multiple alignment analyses amino acid sequences receptor binding domain (HC) eight BoNT/CDs two BoNT/Ds showed sequence clustering five groups. Comparing strain 003-9 (BoNT/CD003-9) 6813 (BoNT/CD6813) that both displayed similar efficacies neurons, but BoNT/CD003-9 model BoNT/CD6813. These findings suggest may be patients who do not respond existing BoNT-based therapeutics.

Language: Английский

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