Type

Journal Article

Authors

Marc Devocelle
Deirdre Fitzgerald-Hughes
Marcus Mall
Hilary Humphreys
Catherine Greene
Emer Reeves
André Schütte
Éanna Forde

Subjects

Microbiology

Topics
bronchoalveolar lavage fluid highly active antimicrobial activity cystic fibrosis antimicrobial peptides antimicrobial peptide inhibitory concentration 50 medicine and health sciences neutrophil elastase drug cytotoxicity lung fibrosis

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis. (2016)

Abstract There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial agents for the treatment of many conditions, including cystic fibrosis (CF). The challenging conditions of the CF patient lung require robust AMPs that are active in an environment of high proteolytic activity but that also have low cytotoxicity and immunogenicity. Previously, we developed prodrugs of AMPs that limited the cytotoxic effects of AMP treatment by rendering the antimicrobial activity dependent on the host enzyme neutrophil elastase (NE). However, cytotoxicity remained an issue. Here, we describe the further optimization of the AMP prodrug (pro-AMP) model for CF to produce pro-WMR, a peptide with greatly reduced cytotoxicity (50% inhibitory concentration against CFBE41o- cells, >300 μM) compared to that of the previous group of pro-AMPs. The bactericidal activity of pro-WMR was increased in NE-rich bronchoalveolar lavage (BAL) fluid from CF patients (range, 8.4% ± 6.9% alone to 91.5% ± 5.8% with BAL fluid; P = 0.0004), an activity differential greater than that of previous pro-AMPs. In a murine model of lung delivery, the pro-AMP modification reduced host toxicity, with pro-WMR being less toxic than the active peptide. Previously, host toxicity issues have hampered the clinical application of AMPs. However, the development of application-specific AMPs with modifications that minimize toxicity similar to those described here can significantly advance their potential use in patients. The combination of this prodrug strategy with a highly active AMP has the potential to produce new therapeutics for the challenging conditions of the CF patient lung.
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Full list of authors on original publication

Marc Devocelle, Deirdre Fitzgerald-Hughes, Marcus Mall, Hilary Humphreys, Catherine Greene, Emer Reeves, André Schütte, Éanna Forde

Experts in our system

1
Marc Devocelle
Royal College of Surgeons in Ireland
Total Publications: 65
 
2
Deirdre Fitzgerald-Hughes
Royal College of Surgeons in Ireland
Total Publications: 31
 
3
Marcus A Mall
Royal College of Surgeons in Ireland
Total Publications: 4
 
4
Hilary Humphreys
Royal College of Surgeons in Ireland
Total Publications: 142
 
5
Catherine M Greene
Royal College of Surgeons in Ireland
Total Publications: 150
 
6
Emer P Reeves
Royal College of Surgeons in Ireland
Total Publications: 63
 
7
Éanna Forde
Royal College of Surgeons in Ireland
Total Publications: 7