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EUR-INTAFAR


Inhibition of new targets for fighting antibiotic resistance
EC contribution
: € 11.301.842
Duration
: 60 months
Starting date
: 01/01/2005
Funding scheme
: Integrated Project
Keywords
: antibiotics, peptidoglycan, bacterial cell morphogenesis, transpeptidase, glycosyltransferase, penicillin-binding proteins, Lipid II, Mur proteins, Fem proteins
Contract/Grant agreement number
: LSHM-CT-2004-512138
Project web-site
: http://www.eur-intafar.eu

Background:

Peptidoglycan (PG) biosynthesis and bacterial cell morphogenesis are related phenomena and are totally specific to bacterial cells without even remotely equivalent systems in eukaryotic cells. The enzymes and proteins involved in these processes are thus promising targets for the design of new antibiotics. Interfering with the activities of the participating enzymes or with the protein-protein interactions that take place along these metabolic pathways should perturb the bacterial cell cycle and, hopefully, supply new weapons to fight dangerous pathogenic organisms such as the methicillin-resistant Staphylococcus aureus (MRSA).


Problem:

Although antibiotics have drastically reduced illness and death from infectious diseases, bacteria have exhibited a remarkable capacity to quickly become resistant to one or several classes of antibiotics. For example, in the US, until 2000, Streptococcus pneumoniae infections caused, each year, 100,000 to 135,000 hospitalisations for pneumonia, 6 million cases of otitis media and 60,000 cases of invasive diseases including 3,300 cases of meningitis. Up to 40% of the infections were caused by bacteria resistant to at least one and 15% to 3 or more antibiotics. The percentage of S. pneumoniae strains resistant to penicillin varies from 3.2 in The Netherlands to 53 in France. Values as high as 60 and 78% are observed in Hong Kong and Saudi Arabia, respectively. Resistance to ?-lactams is often associated to resistance to macrolides.
In 1996, 2 million cases of nosocomial infections were counted annually in US hospitals. Their global cost ranged from 600 $ for a urinary infection to 40,000 $ for a septicemia. Extrapolations made in 1996 in a French study showed that due to nosocomial infections, the stays in hospital were 3 to 7 days longer and the expenses per patient 750 to 1500 higher. These annual extra costs represented about 2% of the total hospital expenses.
Strains isolated from farm animals present even higher levels of resistance. In a recent study performed in Belgium, 95% of the Escherichia. coli strains isolated from poultry, 44% of the strains of bovine origin and 90% strains of porcine origin were resistant to tetracyclines. In all of these cases, resistance to aminoglycosides (streptomycin), chloramphenicol and amoxycillin or ampicillin was also widespread. The increase in antibiotic resistance is thus a global problem, both for nosocomial as well as community-acquired infections. A return to the pre-antibiotic era has even been forecasted. Hence the problem of resistance can only be solved by a multidisciplinary and international approach, which will require a better understanding of the fundamental aspects of bacterial physiology, growth and multiplication mechanisms, areas which have been relatively neglected in the recent past when compared to eukaryotic systems.

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