Carbohydrate-based Inhibitors against Clostridium difficile Toxins

Clostridium difficile infection (CDI) is an important cause of hospital-acquired diarrhea, which results from a major disruption of gut microflora by antibiotics that fail to kill multidrug-resistant C. difficile pathogen. Although uncommon in healthy adults in the general population, the disease is becoming increasingly widespread in Canada, affecting ~10% hospitalized patients. CDI recurs repeatedly in up to 20% of patients, presenting serious challenges to current therapies, and also resulting in significant financial burden to global health systems. At the University of Calgary, during last few years, we have been working with Dr. G. D. Armstrong from Medicine and Dr. K. Ng from Biology to develop novel carbohydrate-based inhibitors to neutralize C. difficile toxins, which are major virulence factors.

The C. difficile bacterium expresses two toxins: toxin A (TcdA) and toxin B (TcdB). Previously, a trisaccharide (αGal(1,3)βGal(1,4)βGlcNAc) was found to bind to TcdA with a low affinity[1]. With the help of Consortium for Functional Glycomics, a pentasaccharide[2-3] has been found to bind to toxin A with high affinity. We have determined the true identify of the leading pentasaccharide using synthesis and X-ray crystollography which also revealed key residues responsible for the binding of the pentasaccharide to toxin A. Currently, we are working on several strategies to obtain novel inhibitors with much improved affinity. Such molecules have the potential to be used as therapeutics to treat CDI.

References

A. Greco, J. G. S. Ho, S.-J. Lin, M. M. Palcic, M. Rupnik and K. K.-S. Ng, Nature Structural & Molecular Biology 13, 460 – 461 (2006). P. Zhang, K. Ng and C.-C. Ling, Org. Biomol. Chem. 8, 128-136 (2010). P. Zhang, N. Razi, L. Eugenio, M. Fentabil, E. Kitova, J. Klassen, D. R. Bundle, K. K.-S. Ng and C.-C. Ling, Chem. Commun. 47, 12397-12399 (2011).