PNEUMOPEP - New methods of treatment of antibiotic-resistant pneumococcal disease

Background:

The advances of the PNEUMOPEP project were 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 (S. pneumoniae) imposes a huge disease burden on humans: it is the number one cause of pneumonia and it is the second 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 from neurological damage after meningitis, due to the acute toxaemia.

The first event in toxaemia is the release of pro-inflammatory or toxic penumococcal products, probably exacerbated by antibiotics. The pneumococcal toxin pneumolysin fulfils both definitions: it is directly toxic to mammalian cells and it stimulates the 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 was a target for this project. A second target was the cell surface proteinases involved in adhesion and invasion, which are important virulence factors for the pneumococcus. These proteins represented new targets and their validation as targets was completed.

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 were evaluated on the basis of binding affinity and neutralising action in vitro. The peptides and small molecules were formulated in chitosan for nasal delivery. Peptides and small molecules were 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.

Problem:

Streptococcus S. pneumoniae imposes a huge disease burden on humans: it is the number one cause of pneumonia and it is the second 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 of neurological damage after meningitis, due to the acute toxaemia.

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