Super toxins from a super bug: structure and function of Clostridium difficile toxins

• Published in: Biochemical journal Vol. 436; no. 3; p. 517
• Main Authors: Davies, Abigail H, Roberts, April K, Shone, Clifford C, Acharya, K Ravi
• Format: Journal Article
• Language: English
• Published: England 15.06.2011
• Subjects: ADP Ribose Transferases - chemistry; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Bacterial Toxins - chemistry; Bacterial Toxins - metabolism; Clostridium difficile - genetics; Clostridium difficile - pathogenicity; Enterotoxins - chemistry; Enterotoxins - metabolism; Glucosyltransferases - chemistry; Protein Structure, Tertiary; rho GTP-Binding Proteins - metabolism; Scattering, Small Angle; X-Ray Diffraction
• ISSN: 1470-8728
• DOI: 10.1042/bj20110106

Clostridium difficile, a highly infectious bacterium, is the leading cause of antibiotic-associated pseudomembranous colitis. In 2009, the number of death certificates mentioning C. difficile infection in the U.K. was estimated at 3933 with 44% of certificates recording infection as the underlying cause of death. A number of virulence factors facilitate its pathogenicity, among which are two potent exotoxins; Toxins A and B. Both are large monoglucosyltransferases that catalyse the glucosylation, and hence inactivation, of Rho-GTPases (small regulatory proteins of the eukaryote actin cell cytoskeleton), leading to disorganization of the cytoskeleton and cell death. The roles of Toxins A and B in the context of C. difficile infection is unknown. In addition to these exotoxins, some strains of C. difficile produce an unrelated ADP-ribosylating binary toxin. This toxin consists of two independently produced components: an enzymatic component (CDTa) and the other, the transport component (CDTb) which facilitates translocation of CDTa into target cells. CDTa irreversibly ADP-ribosylates G-actin in target cells, which disrupts the F-actin:G-actin equilibrium leading to cell rounding and cell death. In the present review we provide a summary of the current structural understanding of these toxins and discuss how it may be used to identify potential targets for specific drug design.