C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability DOI Creative Commons
Santhosh Kumar Nagarajan,

J W Weber,

Daniel Roderer

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 27, P. 287 - 306

Published: Dec. 2, 2024

The pore-forming Clostridium perfringens enterotoxin (CPE), a common cause of foodborne diseases, facilitates Ca2+ influx in enterocytes, leading to cell damage. Upon binding certain claudins (e.g., claudin-4), CPE forms oligomeric pores the membrane. While mechanism CPE-claudin interaction is well understood, structure and assembly pore complex remain elusive. Here, we used AlphaFold2 prediction, alignment, molecular dynamics simulations generate models prepore states CPE/claudin-4 complex. We sequentially addressed CPE-claudin, CPE-CPE, claudin-claudin interactions, along with conformational changes. hexameric variant typical heptameric stem cap architecture aerolysin-like β-barrel toxins (β-PFT). lined three hexa-glutamate rings, which differ from other β-PFTs confer CPE-specific cation selectivity. Additionally, center indicated be anchored by dodecameric claudin ring formed cis-interaction an interface found claudin-based tight junction strands. Mutation residue inhibited CPE-mediated damage vitro. propose that this constitutes anchor for twisting drives extension membrane insertion β-hairpins. Our model agrees previous key experimental data provides insights into structural mechanisms cytotoxic influx.

Language: Английский

Impact of Metabolites from Foodborne Pathogens on Cancer DOI Creative Commons
Alice Njolke Mafe, Dietrich Büsselberg

Foods, Journal Year: 2024, Volume and Issue: 13(23), P. 3886 - 3886

Published: Dec. 1, 2024

Foodborne pathogens are microorganisms that cause illness through contamination, presenting significant risks to public health and food safety. This review explores the metabolites produced by these pathogens, including toxins secondary metabolites, their implications for human health, particularly concerning cancer risk. We examine various such as Salmonella sp., Campylobacter Escherichia coli, Listeria monocytogenes, detailing specific of concern carcinogenic mechanisms. study discusses analytical techniques detecting chromatography, spectrometry, immunoassays, along with challenges associated detection. covers effective control strategies, processing techniques, sanitation practices, regulatory measures, emerging technologies in pathogen control. manuscript considers broader highlighting importance robust policies, awareness, education. identifies research gaps innovative approaches, recommending advancements detection methods, preventive policy improvements better manage foodborne metabolites.

Language: Английский

Citations

11
Antibacterial carbon dots DOI Creative Commons
Shuaishuai Wang, Dapeng Wang, Guoliang Wang

et al.

Materials Today Bio, Journal Year: 2024, Volume and Issue: 30, P. 101383 - 101383

Published: Dec. 6, 2024

Language: Английский

Citations

5
Targeted degradation of α-Synuclein using an evolved botulinum toxin protease DOI Creative Commons

Philipp Sondermann,

Christian S. Diercks,

Cynthia Rong

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(13)

Published: March 24, 2025

There is considerable interest in the targeted degradation of proteins implicated human disease. The use sequence-specific proteases for this purpose severely limited by difficulty engineering numerous enzyme–substrate interactions required to yield highly selective while maintaining catalytic activity. Herein, we report a strategy evolve protease programmed α-Synuclein, presynaptic protein closely linked Parkinson’s Our structure-guided evolution campaign uses from botulinum neurotoxin and showcases stepwise change specificity its native substrate SNAP25 α-Synuclein. protease’s selectivity further demonstrated cells where near complete overexpressed α-Synuclein observed with no significant effects on cell proliferation. This may serve as general approach targeting dysregulated proteins.

Language: Английский

Citations

0
Detoxification Techniques for Bacterial Toxins: A Pathway to Effective Toxoid Vaccines DOI
Parvaneh Esmaeilnejad-Ahranjani, Youcef Shahali, Maryam Dadar

et al.

Toxicon, Journal Year: 2025, Volume and Issue: 260, P. 108365 - 108365

Published: April 17, 2025

Language: Английский

Citations

0
Identification and Dynamics Understanding of Novel Inhibitors of Peptidase Domain of Collagenase G from Clostridium histolyticum DOI Creative Commons
Farah Anjum, Ali Hazazi, Fouzeyyah Ali Alsaeedi

et al.

Computation, Journal Year: 2024, Volume and Issue: 12(8), P. 153 - 153

Published: July 25, 2024

Clostridium histolyticum is a Gram-positive anaerobic bacterium belonging to the genus. It produces collagenase, an enzyme involved in breaking down collagen which key component of connective tissues. However, antimicrobial resistance (AMR) poses great challenge combating infections caused by this bacteria. The lengthy nature traditional drug development techniques has resulted shift computer-aided design and other modern discovery approaches. above method offers cost-effective means for gathering comprehensive information about how ligands interact with their target proteins. objective study create novel, explicit drugs that specifically inhibit C. collagenase enzyme. Through structure-based virtual screening, library containing 1830 compounds was screened identify potential candidates against enzymes. Following that, molecular dynamic (MD) simulation performed aqueous solution evaluate behavior protein ligand environment while density functional theory (DFT) analysis executed predict properties structure lead compounds, WaterSwap technique utilized obtain insights into drug–protein interaction water molecules. Furthermore, principal (PCA) reveal conformational changes, salt bridges express electrostatic stability, absorption, distribution, metabolism, excretion, toxicity (ADMET) assess pharmacokinetics profile top control Three potent were identified MSID000001, MSID000002, MSID000003, binding score −10.7 kcal/mol, −9.8 −9.5 −8 respectively. Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) trajectories revealed energy scores −79.54 −73.99 −62.26 −70.66 correspondingly. exhibited under acceptable range. hold be novel drugs; therefore, further investigation needs conducted find out anti-collagenase action antibiotic resistance.

Language: Английский

Citations

1
Respiratory tract infections: an update on the complexity of bacterial diversity, therapeutic interventions and breakthroughs DOI

Avani Panickar,

Anand Manoharan, Anand Anbarasu

et al.

Archives of Microbiology, Journal Year: 2024, Volume and Issue: 206(9)

Published: Aug. 17, 2024

Language: Английский

Citations

1
Repurposing FDA-approved disulfiram for targeted inhibition of diphtheria toxin and the binary protein toxins of Clostridium botulinum and Bacillus anthracis DOI Creative Commons

Joscha Borho,

Merle Kögel,

Amelie Eckert

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 13, 2024

Many bacteria act pathogenic by the release of AB-type protein toxins that efficiently enter human or animal cells and as enzymes in their cytosol. This leads to disturbed cell functions clinical symptoms characteristic for individual toxin. Therefore, molecules directly target neutralize these provide promising novel therapeutic options. Here, we found FDA-approved drug disulfiram (DSF), used decades treat alcohol abuse, protects from intoxication with diphtheria toxin (DT)

Language: Английский

Citations

0
C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability DOI Creative Commons
Santhosh Kumar Nagarajan,

J W Weber,

Daniel Roderer

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 27, P. 287 - 306

Published: Dec. 2, 2024

The pore-forming Clostridium perfringens enterotoxin (CPE), a common cause of foodborne diseases, facilitates Ca2+ influx in enterocytes, leading to cell damage. Upon binding certain claudins (e.g., claudin-4), CPE forms oligomeric pores the membrane. While mechanism CPE-claudin interaction is well understood, structure and assembly pore complex remain elusive. Here, we used AlphaFold2 prediction, alignment, molecular dynamics simulations generate models prepore states CPE/claudin-4 complex. We sequentially addressed CPE-claudin, CPE-CPE, claudin-claudin interactions, along with conformational changes. hexameric variant typical heptameric stem cap architecture aerolysin-like β-barrel toxins (β-PFT). lined three hexa-glutamate rings, which differ from other β-PFTs confer CPE-specific cation selectivity. Additionally, center indicated be anchored by dodecameric claudin ring formed cis-interaction an interface found claudin-based tight junction strands. Mutation residue inhibited CPE-mediated damage vitro. propose that this constitutes anchor for twisting drives extension membrane insertion β-hairpins. Our model agrees previous key experimental data provides insights into structural mechanisms cytotoxic influx.

Language: Английский

Citations

0