Clostridium difficile infection: molecular pathogenesis and novel therapeutics

Abstract

The Gram-positive anaerobic bacterium Clostridium difficile produces toxins A and B, which can cause a spectrum of diseases from pseudomembranous colitis to C. difficile-associated diarrhea. A limited number of C. difficile strains also produce a binary toxin that exhibits ADP ribosyltransferase activity. Here, the structure and the mechanism of action of these toxins as well as their role in disease are reviewed. Nosocomial C. difficile infection is often contracted in hospital when patients treated with antibiotics suffer a disturbance in normal gut microflora. C. difficile spores can persist on dry, inanimate surface for months. Metronidazole and oral vancomycin are clinically used for treatment of C. difficile infection but clinical failure and concern about promotion of resistance are motivating the search for novel non-antibiotic therapeutics. Methods for controlling both toxins and spores, replacing gut microflora by probiotics or fecal transplant, and killing bacteria in the anaerobic gut by photodynamic therapy are discussed.

Keywords::

• bile acids
• binary toxin
• Clostridium difficile
• fecal transplant
• monoclonal antibody
• pathogenicity locus
• photodynamic therapy
• probiotics
• spore germination
• toxin A and B

Financial & competing interests disclosure

Research in the Hamblin laboratory is supported by US NIH grant R01AI050875. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The numbers of deaths and the costs associated with Gram-positive Clostridium difficile infections (CDIs) are increasing.

• Metronidazole and vancomycin are the first-line therapy for CDIs but treatment failures and recurrences are increasing.

• Although new macrocyclic antibiotics are under investigation for CDI therapy, the disruption of microflora is a major issue after antibiotic treatments.

• Monoclonal antibodies have been shown to be an effective non-antibiotic approach against CDIs.

• Vegetative cells produce spores that can stay for a long time in hospital environments and germination in patients is controlled by bile salts.

• Fecal transplant is a new alternative therapy that may gain traction in the near future.

• In the future, photodynamic therapy may be effective in the anaerobic environment of the colon since photosensitizer such as EtNBS may act in an oxygen-independent manner.

Notes