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COBRA


Combating resistance to antibiotics by broadening the knowledge on molecular mechanisms behind resistance to inhibitors of cell wall synthesis
EC contribution
: € 2.980.000
Duration
: 36 months
Starting date
: 01/02/2004
Funding scheme
: Specific Targeted Research Project
Keywords
: resistance to antibiotics, cell wall synthesising machinery, PBP, non-PBP factors and resistance , ß-lactamases, catalytic mechanisms, structural studies, gene acquisition and mobility, Gram- positive and -negative organisms
Contract/Grant agreement number
: LSHM-CT-2003-5003335
Project web-site
: -

Background:

We have aim at the elucidation of the molecular mechanisms of resistance to inhibitors of cell wall synthesis in bacteria responsible for severe nosocomial and community-acquired infections. Our STREP was focused on -lactams, the major class of antibiotics in current clinical use, and on resistance due to modifications of the cell wall synthesizing machinery and to production of ß-lactamases, the most prevalent mechanisms in Gram-positive and Gram-negative bacteria, respectively. These studies form a reference to globally assess the modifications of the structure, function, and dynamics of the peptidoglycan assembly pathways responsible for emergence of resistance including the 3 D structure of relevant components and possible targets. It has identify new ß-lactamases, determine their 3 D structure and elucidate different aspects of the regulation of their gene expression and the mechanisms responsible for their mobility.


Problem:

Antibiotics are not like other drugs in that they act against bacteria and not the human host. Therefore the evolution of resistance under the selective pressure of antibiotics after exposure of populations (human, animal) raises major therapeutical issues. This program addresses the general problem of resistance to antibiotics and concerns the understanding of the mechanisms of resistance, in particular to inhibitors of cell wall synthesis. Among these are the ß-lactams, one of the most important classes of antibiotics, if not the most broadly used antibiotics worldwide. The rates of ß-lactam resistance for many common species found in infections have reached high levels in the community, as well as in the hospital. While In Gram-positive organisms this resistance is mainly due to altered targets, in Gram-negative organisms, acquired resistance to ß-lactams is essentially due to the presence of plasmid-encoded ß-lactamases or the over-expression of chromosome-encoded ß-lactamases. This latter resistance can be enhanced by associated impermeability or efflux mechanisms. Since many pathogens are multiresistant, there will be an eventual limitation in the choice of antibiotics useful for primary treatment and therefore a promotion of a vicious cycle facilitating the emergence of new resistances.

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