Institut Pasteur Unit\351 de G\351n\351tique Mol\351culaire

Mycobacteria: Genomics, BACs and Resistance
Recent Publications
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Genomics, antibiotic resistance and pathogenesis of the Clostridia

Clostridium perfringens and Clostridium difficile are pathogenic anaerobic bacteria of importance in human and veterinary medicine.
Our recent work on C. perfringens, the etiologic agent of diseases ranging from mild food poisoning to necrotic enteritis and gas gangrene, has focused mainly on structure-function studies and cytotoxicity of the alpha toxin (phospholipase C) and the urease found in certain strains, particularly those associated with invasive disease in domesticated livestock. Currently, we are investigating the molecular basis of the response of this bacterium to oxidative stresses such as those imparted by superoxides and hydroxide radicals, and its ability to survive in an aerobic environment which likely represents an important virulence factor.

The pathogenesis of C. difficile, the bacterium responsable for life-threatening pseudomembranous colitis and the majority of antibiotic-associated diarrhoeas, is mainly due to the production and activity of two potent toxins, ToxA and ToxB. We have undertaken an in-depth study of the control mechanisms governing transcription of the toxA et toxB genes, and this has highlighted the importance of the regulatory protein TxeR in their expression and thus in disease. In collaboration with a group at the Hôpital Saint-Antoine, we are examining a panel of clinical isolates of C. difficile displaying resistance to the front-line drug, metronidazole, that have recently emerged.

Further reading:

Dupuy, B., Mani, N., Katayama, S., and Sonenshein, A.L.(2005) Transcription activation of a UV-inducible Clostridium perfringens bacteriocin gene by a novel sigma factor. Mol Microbiol. 55:1196-206.

Raffestin, S. Dupuy, B., Marvaud, J.C., and Popoff, M.R. (2005). BotR/A and TetR are alternative RNA polymerase sigma factors controlling the expression of the neurotoxin and associated protein genes in Clostridium botulinum type A and Clostridium tetani. Mol. Microbiol. 55, 235-249 .

Rupnik, M., Dupuy, B., Fairweather, N.F., Gerding, D.N., Johnson, S., Just, I., Lyerly, D.M., Popoff, M.R., Rood, J.I., Sonenshein, A.L., Thelestam, M., Wren, B.W., Wilkins, T.D. and von Eichel-Streiber C. (2005) Revised nomenclature of Clostridium difficile toxins and associated genes. J Med Microbiol 54: 113-117.

Raffestin, S., Marvaud, J.C., Cerrato, R., Dupuy, B. and Popoff, M .R. (2004).Organization and regulation of the neurotoxin genes in Clostridium botulinum and Clostridium tetani. Anaerobe 10: 93-100.

Karlsson, S., Dupuy, B., Mukherjee, K., Norin, E., Burman, L.G., and Akerlund, T. (2003) Expression of Clostridium difficile toxins A and B and their sigma factor TcdD is controlled by temperature. Infect Immun. 71:1784-93.

Mani, N., Lyras, D., Barroso, L., Howarth, P., Wilkins, T., Rood, J. I., Sonenshein, A. L., and Dupuy, B. (2002) Environmental response and autoregulation of Clostridium difficileTxeR, a sigma factor for toxin gene expression. J Bacteriol. 184:5971-8, (pdf).

Mani N, Dupuy B. (2001) Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor. PNAS 98:5844-9 .

As part of the unit's genomic activities, ordered BAC libraries (vector pBeloBAC11 kindly provided by Dr. Shizuya at the California Institute of Technology) of C. difficile strain 630 (epidemic type X ) and C. perfringens strain 13 have been produced.

Useful Link: Clostridium difficile genome projectat the Sanger Centre.

Please address questions and comments to Bruno DUPUY

Institut Pasteur Unité de Génétique Moléculaire