Marc Devocelle
Royal College of Surgeons in Ireland, Ireland
Title: Antimicrobial peptide prodrugs activated by neutrophil elastase
Biography
Biography: Marc Devocelle
Abstract
For millions of years, the first line of defense against infections in multicellular organisms has relied on peptides with cationic and amphipathic properties. These Antimicrobial Peptides (AMPs) represent promising leads for the development of antibiotics delaying the emergence of resistance in bacteria. However, their clinical applications have been limited by inadequate margins of safety. A prodrug approach can overcome a toxicity barrier in drug delivery. With AMPs, prodrugs can be generated by reducing their net positive charge, through a modification which can be selectively removed by an enzyme (bacterial or human) confined to sites of infection. For example, neutrophil elastase (NE), a human protease involved in chronic airway inflammation and infections associated with cystic fibrosis (CF) can disconnect an oligo-glutamate promoiety masking the net positive charge and therefore activity of AMP candidates (Bac8c, P18, HB43, WMR and WR12). Their bactericidal activities against reference and clinical isolates of the CF pathogen P. aeruginosa are restored by NE in CF bronchoalveolar lavage fluids. Toxicity differentials are also achieved with the active peptides consistently more hemolytic and cytotoxic against representative epithelial and immune cells than their prodrug forms with the exception of WMR. While no toxicity was observed in vitro with both active and prodrug forms of this candidate, in vivo studies indicated that the prodrug was better tolerated than the active peptide. Finally, an in vitro nebulization study performed with a vibrating mesh nebulizer showed that a high level of dosing in the lung can be achieved for this AMP prodrug