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.
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
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.
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
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.