Article
Biochemistry & Molecular Biology
Florian Stieglitz, Ralf Gerhard, Rabea Hoenig, Klaudia Giehl, Andreas Pich
Summary: A Clostridioides difficile infection (CDI) is a common hospital-acquired infection worldwide. The virulence factors TcdA and TcdB inhibit small Rho-GTPases, leading to cytopathic effects, colon epithelium barrier dysfunction, and inflammation. A large-scale phosphoproteomic study revealed the central role of RAS in the glucosyltransferase-independent effect of TcdB, and identified apolipoprotein C-III (APOC3) as a potential crucial factor in CDI-induced inflammation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Sebastian Heber, Lara Barthold, Jan Baier, Panagiotis Papatheodorou, Giorgio Fois, Manfred Frick, Holger Barth, Stephan Fischer
Summary: C. difficile produces toxins TcdA and TcdB, which cause CDAD by targeting small GTPases and disrupting intestinal epithelial barrier. Conventional antibiotics do not target these toxins, therefore directly targeting the exotoxins provides a promising treatment approach. Recent findings show that ambroxol reduces toxin-induced cytotoxicity and glucosylation, and could be considered as a therapeutic option for CDAD.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biotechnology & Applied Microbiology
Mojtaba Moosavian, Razieyeh Keshavarzi, Effat Abbasi Montazeri, Eskandar Hajiani
Summary: This study investigated the prevalence of Clostridioides difficile in patients with suspected C. difficile infections using culture, M-PCR, and LAMP methods. The results showed that the LAMP assay is a good method for direct detection of toxigenic C. difficile strains from stool specimens.
Article
Immunology
Baohua Chen, Kay Perry, Rongsheng Jin
Summary: This study reports the identification of two critical epitopes on the virulence factor TcdA and sheds new insights into the neutralizing mechanisms of two potent camelid antibodies against TcdA. These findings provide potential targets for the development of epitope-focused vaccines against TcdA.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Microbiology
Hamideh Raeisi, Masoumeh Azimirad, Hamid Asadzadeh Aghdaei, Amir-Hassan Zarnani, Jalal Abdolalizadeh, Abbas Yadegar, Mohammad Reza Zali
Summary: In this study, phage display was used to select single-chain variable fragments (scFvs) that specifically target the major virulence factors, TcdA and TcdB, of Clostridioides difficile. The selected scFvs showed high neutralizing activity and could decrease the mRNA expression of inflammatory markers in treated cells. Molecular docking revealed that the interaction between scFvs and toxins was mainly restricted to the CROP domain. These findings provide insights for the development of neutralizing scFvs against C. difficile toxins using phage display.
MICROBIOLOGY SPECTRUM
(2023)
Article
Infectious Diseases
Guido Granata, Davide Mariotti, Paolo Ascenzi, Nicola Petrosillo, Alessandra di Masi
Summary: The study demonstrates that toxemia is more common than expected in patients with Clostridioides difficile infection, and specifically that high serum levels of TcdA are correlated with disease severity.
Article
Biochemistry & Molecular Biology
Lara Barthold, Sebastian Heber, Christoph Q. Schmidt, Marion Gradl, Gilbert Weidinger, Holger Barth, Stephan Fischer
Summary: Rising incidences and mortalities of Clostridioides difficile infections (CDIs) have raised concerns. In this study, the protective effect of human antimicrobial peptide alpha-defensin-6 against CDI toxins TcdA and TcdB was demonstrated. The peptide prevented toxin-mediated glucosylation of Rho-GTPases, protecting cells, epithelial barriers, and zebrafish embryos from toxic effects. It was found that alpha-defensin-6 rapidly sequesters the toxin into complexes, preventing its cytotoxic activity. These findings contribute to the understanding of how human peptides neutralize bacterial protein toxins and may guide the development of novel therapeutic options against CDIs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Microbiology
Isabel Marquardt, Josefine Jakob, Jessica Scheibel, Julia Danielle Hofmann, Frank Klawonn, Meina Neumann-Schaal, Ralf Gerhard, Dunja Bruder, Lothar Jaensch
Summary: C. difficile toxins can efficiently activate human mucosal-associated invariant T (MAIT) cells, especially CDTb provokes significant activation. This response partially depends on MR1 and monocytes, and may contribute to the pathophysiology of CDAC by inducing cytotoxicity.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Food Science & Technology
Aria Aminzadeh, Rene Jorgensen
Summary: By optimizing culture parameters and purification methods, the production yield of native toxin A and toxin B from Clostridioides difficile was significantly improved, resulting in high concentrations of toxin B. Additionally, optimal conditions for improving protein stability during storage were identified.
Review
Biochemistry & Molecular Biology
Nashwa El Hadidy, Vladimir N. Uversky, Xingmin Sun
Summary: This paper offers an overall review of the structural and functional differences between major toxins TcdA and TcdB of C. difficile, and suggests that intrinsic disorder may play a role in their pathogenic mechanisms.
CURRENT PROTEIN & PEPTIDE SCIENCE
(2022)
Article
Medicine, Research & Experimental
Khalid M. Aljarallah, Sezanur Rahman
Summary: This study identified potential antagonists for the two major toxins of Clostridium difficile, TcdA and TcdB, from a library of plant-derived compounds through computational screening. The top 10 compounds for each target were found to have higher binding affinities compared to their positive controls, suggesting them to be good drug candidates against C. difficile toxins. Further validation with in vivo and in vitro experiments is needed before considering these potential inhibitors as prospective therapeutics.
INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE
(2021)
Article
Microbiology
Xiaojun Hu, Renhan Dong, Sheng Huang, Yisheng Zeng, Wei Zhan, Xiaofang Gao, Dong Tian, Jian Peng, Jiewei Xu, Ting Wang, Yaying Zhang, Xiaohui Wang, Xiaoxia Zhang, Jin Liu, Bing Guang, Tai Yang
Summary: The novel small-molecule compound CDBN-YGXZ, synthesized by modifying nitazoxanide with lauric acid, inhibits the proliferation of Clostridioides difficile by inhibiting the activity of PFOR. In the CDI models of mice and hamsters, CDBN-YGXZ shows protective effects and can reduce or prevent CDI relapse, with significant clinical scores. Compared to vancomycin, CDBN-YGXZ has the potential to be developed as a candidate drug for treating CDI.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)