Pneumolysin (PLY) is a proven virulence factor of Streptococcus pneumoniae, deeply involved in the development of pneumococcal invasive diseases. The antibacterial and adjunctive therapies currently used in the management of pneumococcal infection do not address the pneumolysin-induced cytotoxicity. Therefore, even if patients survive the infection, they may suffer from long-term disabilities as a consequence of the exposure to the toxin. This research seeks to address this problem by developing new approaches to the treatment of pneumococcal diseases, based on peptides or small molecules that target pneumolysin and inhibit its activity. The peptides and small molecules were evaluated for their capacity to inhibit the haemolytic activity of pneumolysin in vitro. In total, four peptides and six small molecules were selected for in vivo tests. In vivo experiments were performed using a pneumonia model, where each animal was administered PBS or peptide / small molecule in PBS intranasally, every 6 hours after intranasal infection. One peptide (P1) and three small molecules (SM6, SM10 and SM14) improved significantly the outcome of the treatment group over the control group, when looking at the CFU in the blood, disease sign score and survival comparison. Moreover, two small molecules (SM10 and SM14) tested ex vivo, showed the capacity to abolish pneumolysin cytotoxic effect on the ciliary function of rat ependymal cells. The pneumolysin inhibitors identified in this work were pointed as potential candidates to further testing in drug discovery.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:602658 |
| Date | January 2014 |
| Creators | Pires Damaso, Mafalda |
| Contributors | Andrew, Peter; O'Callaghan, Christopher |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/28799 |
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