Clostridium difficile Toxins A and B: Insights into Pathogenic Properties and Extraintestinal Effects

Abstract

Clostridium difficile infection (CDI) has significant clinical impact especially on the elderly and/or immunocompromised patients. The pathogenicity of Clostridium difficile is mainly mediated by two exotoxins: toxin A (TcdA) and toxin B (TcdB). These toxins primarily disrupt the cytoskeletal structure and the tight junctions of target cells causing cell rounding and ultimately cell death. Detectable C. difficile toxemia is strongly associated with fulminant disease. However, besides the well-known intestinal damage, recent animal and in vitro studies have suggested a more far-reaching role for these toxins activity including cardiac, renal, and neurologic impairment. The creation of C. difficile strains with mutations in the genes encoding toxin A and B indicate that toxin B plays a major role in overall CDI pathogenesis. Novel insights, such as the role of a regulator protein (TcdE) on toxin production and binding interactions between albumin and C. difficile toxins, have recently been discovered and will be described. Our review focuses on the toxin-mediated pathogenic processes of CDI with an emphasis on recent studies.

Bacterial proteases, untapped antimicrobial drug targets

“…These toxins are composed of three domains: a receptor binding domain that targets the toxins to the host epithelial cell surface, a Cys protease domain that activates the toxin following endocytosis and a glucosytransferase domain that glucosylates Rho and Rac family GTPases, resulting in toxic downstream effects on the cell. 103 A screen for inhibitors of the Cys protease domain identified the organo-selenide ebselen. 104 Ebeselen efficiently blocked Cys protease activity of C. difficile toxins TcdA and TcdB in vitro and in cell culture, and also demonstrated protective activity in a mouse model of infection.…”

Bacterial defiance as a form of prodrug failure

“…Cationic AMPs act by disrupting bacterial membranes and inducing inflammatory responses 13 , but suffer from off-target toxicity and low stability in vivo 14,15 . Our AMP prodrugs are activated directly by bacterial proteases, which are a major cause of virulence [16][17][18][19][20][21] during infections and important targets for antibiotic development 22 . Of these proteases, outer membrane protease T (OmpT) is a membrane-bound 5 bacterial protein that is widely conserved across gram-negative bacteria of the Enterobacteriaceae family and recognizes a variety of targets that contribute to its virulence (e.g., plasminogen) 18,19,[23][24][25] .…”

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

“…This domain inactivates specific enzymes such as the Rho GTPases through glycosylation. This leads to both cytopathic and cytotoxic downstream effects by altering the cytoskeletal structure, epithelial permeability, and cell‐to‐cell junctions, as well as by activating the inflammasome and apoptosis . With the destruction of the epithelium, C. difficile infection can cause diarrhea and lead to complicated cases through systemic effects such as sepsis, shock, peritonitis, and bowel perforation as the intestine becomes compromised.…”