Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS


COBRA Sintesi della relazione

Project ID: 503335
Finanziato nell'ambito di: FP6-LIFESCIHEALTH
Paese: France

Final Report Summary - COBRA (Combating resistance to antibiotics by broadening the knowledge on molecular mechanisms behind resistance to inhibitor of cell wall synthesis)

The goal of COBRA was to better understand the various mechanisms of resistance to inhibitors of cell wall synthesis, in particular b-lactams, and to decipher recently appeared mechanisms of resistance. Research focused on various bacteria of clinical importance, including Gram-negative bacteria, and members of the family Enterobacteriaceae and Pseudomonas aeruginosa, as well as Gram-positive bacteria including Staphylococcus aureus, Streptococcus pneumonia, Enterococcus faecalis, and Enterococcus faecium. These bacteria are responsible for severe community-acquired and nosocomial infections.

Most of the mechanisms of resistance explored in this specific targeted research project (STREP) were either natural or acquired in the patient due to the selective pressure associated with the vast consumption of antibiotics. Partners also characterised mutants selected in vitro to anticipate the emergence of new mechanisms of resistance. They explored the mechanisms related to the modifications of essential targets, and associated critical factors connected with the expression of resistance, as well as the mechanisms of resistance due to enzymatic inactivation and decreased permeability.

This resulted in the improved knowledge:
i) of the structure-function studies of different penicillin target D,D-transpeptidases (PBPs);
ii) of the enzymology of lipid-linked steps of peptidoglycan biosynthesis and identification of new enzymes among which some bypass the normal pathway of the peptidoglycan biosynthesis resulting in new peptidoglycan structures and resistance;
iii) many new emerging beta-lactamases of class A,B,C and D whose diversities, environments, structures and three-dimensional (3D) structure/activity relationships were determined.

The project's comprehensive approaches to determine the bacterial mechanisms of resistance to cell wall synthesis inhibitors should help clinical and industrial organisations involved in bacteriology. Exploitation of the results obtained will likely be translated directly to the clinic as far as epidemiological surveys and recognition of new phenotypes are concerned. A longer delay was considered necessary to translate studies of some of the potential interesting targets into practice.

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