Novel antimicrobial peptides to fight infections in patients with cystic fibrosis

Abstract

Objectives: In view of the current limitations to treat and reduce pulmonary infections and chronic inflammation in Cystic Fibrosis (CF) patients effectively, we explored the potential of a novel therapeutic approach based upon antimicrobial peptides (AMPs). Novel cathelicidin-like peptides have been designed and were tested for their antimicrobial and cytotoxic properties in vitro and ex vivo. Methods: Several well-established microbiological assays (colony counts, bioscreen kinetics) were applied using different media to test the killing efficacy of the different peptide designs against several isolates of CF-relevant bacterial and fungal species. Different mammalian cell culture systems (bronchial cell lines, primary human nasal cells) were used to screen for toxicity using the WST-1 conversion assay (cell viability). Results: Newly developed AMPs were found to display extraordinary strong antimicrobial activities against several clinical isolates of multi-resistant Pseudomonas aeruginosa and Staphylococcus aureus and were shown to be effective against pathogens present in CF-patient-derived pulmonary lavage and sputum. In addition, these peptides possessed strong antifungal properties against Candida albicans and Aspergillus fumigatus, two important fungal pathogens associated with CF. In vitro studies revealed that these AMPs are active under physiological conditions (in the presence of NaCl, CaCl2) and at the lower pH that typically exists in theCFlung. Furthermore, these peptides exhibitedlowcytotoxicity towards several mammalian cell types (e.g. primary human nasal epithelial cells). Conclusion: Novel cathelicidin-inspired peptides show potential as a new anti-infectious therapy to effectively reduce a broad-range of microbial infections in the upper and lower airways of patients suffering from CF. This novel therapeutic approach may help to limit pulmonary inflammation and tissue damage, and will improve clinical outcome in CF-patients.