Clostridioides difficile: Current overview and future perspectives

Giles, Joanna; Roberts, April K.

doi:10.1016/bs.apcsb.2021.11.003

Cited by 8 publications

(10 citation statements)

References 112 publications

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“…Gastrointestinal infections are a major public health issue. In high-income countries, the Grampositive spore forming anaerobe Clostridioides difficile is the leading cause of nosocomial diarrhea and colitis in adults receiving antibiotic treatments (1,2). Moreover, C. difficile infections (CDI) can be persistent, which is a major challenge in the management of CDI following anti-C. difficile antibiotic treatment.…”

Section: Introductionmentioning

confidence: 99%

The cell wall lipoprotein CD1687 acts as a DNA binding protein during deoxycholate-induced biofilm formation inClostridioides difficile

Auria¹,

Hunault

England

et al. 2022

Preprint

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The ability of bacterial pathogens to establish recurrent and persistent infections is frequently associated with their ability to form biofilms. Clostridioides difficile infections have a high rate of recurrence and relapses and it is hypothesised that biofilms are involved in its pathogenicity and persistence. Biofilm formation by C. difficile is still poorly understood. It has been shown that specific molecules such as deoxycholate (DCA) or metronidazole induce biofilm formation, but the mechanisms involved remain elusive. In this study, we describe the role of the C. difficile lipoprotein CD1687 during DCA-induced biofilm formation. We showed that the expression of CD1687, which is part of an operon within the CD1685-CD1689 gene cluster, is controlled by multiple transcription starting sites and some are induced in response to DCA. Only CD1687 is required for biofilm formation and the overexpression of CD1687 is sufficient to induce biofilm formation. Using RNAseq analysis, we showed that CD1687 affects the expression of transporters and metabolic pathways and we identified several potential binding partners by pull-down assay, including transport-associated extracellular proteins. We then demonstrated that CD1687 is surface exposed in C. difficile, and that this localization is required for DCA-induced biofilm formation. Given this localization and the fact that C. difficile forms eDNA-rich biofilms, we confirmed that CD1687 binds DNA in a non-specific manner. We thus hypothesize that CD1687 is a component of the downstream response to DCA leading to biofilm formation by promoting interaction between the cells and the biofilm matrix by binding eDNA.

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Section: Introductionmentioning

confidence: 99%

The cell wall lipoprotein CD1687 acts as a DNA binding protein during deoxycholate-induced biofilm formation inClostridioides difficile

Auria¹,

Hunault

England

et al. 2022

Preprint

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“…CDT is less well characterized: C. difficile strains expressing CDT only seem unable to cause disease but strains expressing the three toxins are associated with the risk of severe disease [15]. Release of cytokines and cell death leads to inflammation and further disruption of the mucosal layer [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Treatments such as administration of antibiotics can be responsible for dysbiosis [3], an imbalance in the gut microbiome composition that has the potential to produce intestinal disease and is present in colorectal cancer (CRC) patients [4]. Clostridioides difficile (C. difficile) is the causative agent of infectious diarrhoea and other intestinal diseases such a pseudomembranous colitis, toxic megacolon, transmural pan-colitis that may require colectomy, and life-threatening fulminant infection [5,6], which most often occur after antibiotic treatment [7,8]. This toxin-producing member of the Firmicutes phylum is responsible for the majority of healthcare-associated gastrointestinal infections [8][9][10][11], and is associated with relevant health care costs [12].…”

Section: Introductionmentioning

confidence: 99%

Clostridioides difficile and colorectal cancer: a dangerous liaison

Bassotti

Stracci

Marconi

et al. 2023

European Journal of Gastroenterology &Amp; Hepatology

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Many colorectal diseases depend on complex interactions between several pathophysiological factors, including the intestinal microbiota. In recent years, the widespread use of antibiotics has been recognized as a main cause of intestinal dysbiosis and a favouring factor for Clostridioides difficile infection. The latter, in addition, causes infectious diarrhoea, pseudomembranous colitis, and toxic megacolon by means of its toxins (A and, especially, B), is characterized by frequent relapses; thus, its persistence in a host may be long-lasting. Based on recent experimental evidence, here we analyse the possibility that, similarly to other bacteria, Clostridioides difficile may be considered a potential carcinogen for colorectal cancer.

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“…Antibiotics including metronidazole, vancomycin, and fidaxomicin are currently the primary treatment options for CDI. However, up to 30% of patients suffer a recurrence following initial antibiotics therapy and the risks of additional recurrences also increase ( 4 ), which raises the urgent need to develop more effective therapeutics for CDI treatments.…”

Section: Introductionmentioning

confidence: 99%

“…Two high-molecular-weight exotoxins, toxin A (TcdA) and toxin B (TcdB), secreted by C. difficile are the major virulence factors responsible for CDI, which lead to a wide spectrum of clinical symptoms ranging from mild diarrhea to life threatening pseudomembranous colitis ( 4 – 7 ). The sequences and three dimensional structures of TcdA and TcdB show a similar modular arrangement which could be divided into four functional domains: an amino-terminal glucosyltransferase domain (GTD), a cysteine protease domain (CPD), a delivery and receptor-binding domain (DRBD), and a carboxy-terminal combined repetitive oligopeptides domain (CROPs) ( 8 – 10 ) ( Figure 1A ).…”

Section: Introductionmentioning

confidence: 99%

Neutralizing epitopes on Clostridioides difficile toxin A revealed by the structures of two camelid VHH antibodies

2022

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Toxin A (TcdA) and toxin B (TcdB) are two key virulence factors secreted by Clostridioides difficile, which is listed as an urgent threat by the CDC. These two large homologous exotoxins are mainly responsible for diseases associated with C. difficile infection (CDI) with symptoms ranging from diarrhea to life threatening pseudomembranous colitis. Single-domain camelid antibodies (VHHs) AH3 and AA6 are two potent antitoxins against TcdA, which when combined with two TcdB-targeting VHHs showed effective protection against both primary and recurrent CDI in animal models. Here, we report the co-crystal structures of AH3 and AA6 when they form complexes with the glucosyltransferase domain (GTD) and a fragment of the delivery and receptor-binding domain (DRBD) of TcdA, respectively. Based on these structures, we find that AH3 binding enhances the overall stability of the GTD and interferes with its unfolding at acidic pH, and AA6 may inhibit the pH-dependent conformational changes in the DRBD that is necessary for pore formation of TcdA. These studies reveal two functionally critical epitopes on TcdA and shed new insights into neutralizing mechanisms and potential development of epitope-focused vaccines against TcdA.

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Clostridioides difficile: Current overview and future perspectives

Cited by 8 publications

References 112 publications

The cell wall lipoprotein CD1687 acts as a DNA binding protein during deoxycholate-induced biofilm formation inClostridioides difficile

The cell wall lipoprotein CD1687 acts as a DNA binding protein during deoxycholate-induced biofilm formation inClostridioides difficile

Clostridioides difficile and colorectal cancer: a dangerous liaison

Neutralizing epitopes on Clostridioides difficile toxin A revealed by the structures of two camelid VHH antibodies

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