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New methods of treatment of antibiotic-resistant pneumococcal disease

Objective

The innovations of this project are the new targets, identification of completely new lead compounds, a new approach to adjunctive therapy and a new method of delivery of the compounds. Streptococcus pneumoniae imposes a huge disease burden on humans: it is the number one cause of pneumonia and it is the sed most common cause of meningitis. There is a pandemic of multi-drug resistant pneumococci and treatment is compromised. Even if antibiotics kill the bacterium, they can fail to prevent death or neurological damage after meningitis, due to the acute toxaemia. The first event in toxaemia is release of pro-inflammatory or toxic pneumococcal products, probably exacerbated by antibiotics. The pneumococcal toxin pneumolysin fulfils both definitions: it is directly toxic to mammalian cells and it stimulates release of inflammatory mediators from host cells. For this reason and because the toxin is essential for the survival of the bacterium in vivo, pneumolysin will be a target of this project A sed target will be the cell surface proteinases involved in adhesion and invasion, which are important virulence factors for the pneumococcus. These proteins represent new targets and their validation as targets has been done. The new treatment will be based on binding peptides isolated from a series of large phage display libraries or based on small molecules identified by high throughput screening. Following screening of the phage libraries the most promising peptides will be evaluated on the basis of binding affinity and neutralising action in vitro. The peptides and small molecules will be formulated in chitosan for nasal delivery. Peptides and small molecules will be tested in animal models of pneumonia, bacteraemia and meningitis, with and without antibiotics. We present our preliminary data showing that a peptide can be used to treat pneumococcal disease. These data underline the capacity of the sortium to achieve the project objectives.

Call for proposal

FP6-2003-LIFESCIHEALTH-I
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Coordinator

UNIVERSITY OF LEICESTER
Address
University Road
Leicester
United Kingdom

Participants (4)

UNIVERSITA DEGLI STUDI DI SIENA
Italy
Address
Via Banchi Di Sotto 55
Siena
UNIVERSITÀ DEGLI STUDI DI MESSINA
Italy
Address
Piazza Pugliatti 1
Messina
ARCHIMEDES DEVELOPMENT LTD
United Kingdom
Address
Nottingham Science. & Technology Park, University Boulevard
Nottingham
ESSAIS CLINIQUES-EVALUATION-EPIDÉMIOLOGIE-STATISTIQUES
France
Address
49 Rue Auguste Lançon
Paris