Antibacterial Agents


  HEADProf. COURVALIN Patrice / pcourval@pasteur.fr
  MEMBERSCOYNE Sébastien / Dr DEPARDIEU Florence / FOUCAULT Marie-Laure / Dr GALIMAND Marc
Dr GRILLOT-COURVALIN Catherine / Prof. LAMBERT Thierry / Dr PERICHON Bruno


  Annual Report

Introduction

The Unité des Agents Antibactériens studies the genetic basis, biochemical mechanisms, heterologous expression, evolution, and dissemination of antibiotic resistance in bacteria pathogenic for humans.

Antibiotic resistance by modulation of gene expression. Vancomycin resistance by remodeling of peptidoglycan synthesis in Gram-positive cocci and intrinsic multidrug resistance in Acinetobacter by efflux are under the control of two-component systems. We are studying constitutive clinical isolates selected under therapy that are mutated in the sensor or in the regulator as well as a new tri-component regulatory system in Enterococcus. We are also developing a biochip for the detection of multiple resistance in Acinetobacter.

Biological cost and dissemination of vancomycin resistance. We are evaluating, in vitro and in vivo, the biological cost of vancomycin resistance in Enterococcus and the consequence on its dissemination. A dual bioluminescence system will allow comparison of the isogenic strains constructed. Vancomycin resistance in methicillin-resistant Staphylococcus aureus (MRSA) is due to acquisition of the vanA operon from Enterococcus. We have shown strong synergism between these two drugs suggesting, surprisingly, that their combination might be useful for the treatment of infections due to VanA-type MRSA.

Aminoglycoside resistance by ribosomal 16S rRNA methylation. We have detected high-level resistance to all clinically available aminoglycosides in enterobacteria and demonstrated that this was due to methylation of the N7 position of nucleotide G1405 in the 16S rRNA. Methylation at this position was shown to mediate resistance by blocking aminoglycoside binding by ribosomes. The gene for a methylase was born by a plasmid which also conferred resistance to fluoroquinolones by efflux. The latter represents a new transferable resistance mechanism to this class of drugs.

Resistance island in Pseudomonas aeruginosa. We are completing the characterization of a genomic island conferring multidrug resistance in P. aeruginosa. Indirect congruent evidence suggests that this island is the progenitor of that in epidemic Salmonella typhimurium DT104.

Gene and protein transfer from an E. coli derived bacterial vector to mammalian cells. Recent development has dealt with cell delivery of large (> 150 kb) bacterial artificial chromosomes. Protein delivery is exploited for stimulation of mucosal immunity in vaccines delivered by the nasal route.

Centre National de Référence des Antibiotiques (CRAB). The public health missions of the CRAB, assigned by the French Health Ministry, consist in maintenance of strain collections, evaluation of the activity of new antibiotics, development of reference in vitro susceptibility tests, and contribution to surveillance of resistance.

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Picture 1. Antibiogram of a Klebsiella pneumoniae harbouring the armA gene. The Arms protein confers resistance to amikacin, netilmicin, tobramycin, gentamicin, kanamycin and fortimicin, but not to neomycin and apramycin.
Picture 2. Oxacillin-glycopeptide synergism against a VanA-type MRSA by disk-agar diffusion. Ox, oxacillin ; Tec, teicoplanine ; Va, vancomycin.



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More informations on our web site


  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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