Abstract
Patients with cystic fibrosis require pharmacological treatment against chronic lung infections. The alpha-helical antimicrobial peptides BMAP-27 and BMAP-28 have shown to be highly active in vitro against planktonic and sessile forms of multidrug-resistant Pseudomonas aeruginosa, Staphylococcus aureus, and Stenotrophomonas maltophilia cystic fibrosis strains. To develop small antibacterial peptides for therapeutic use, we tested shortened/modified BMAP fragments, and selected the one with the highest in vitro antibacterial activity and lowest in vivo acute pulmonary toxicity. All the new peptides have shown to roughly maintain their antibacterial activity in vitro. The 1–18 N-terminal fragment of BMAP-27, showing MIC90 of 16 µg/ml against P. aeruginosa isolates and strain-dependent anti-biofilm effects, showed the lowest pulmonary toxicity in mice. However, when tested in a murine model of acute lung infection by P. aeruginosa, BMAP-27(1–18) did not show any curative effect. If exposed to murine broncho-alveolar lavage fluid BMAP-27(1–18) was degraded within 10 min, suggesting it is not stable in pulmonary environment, probably due to murine proteases. Our results indicate that shortened BMAP peptides could represent a starting point for antibacterial drugs, but they also indicate that they need a further optimization for effective in vivo use.
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Acknowledgments
This study was entirely supported by Fondazione per la Ricerca sulla Fibrosi Cistica-Onlus, Verona, Italy (FFC Projects 11#2012 and 14#2014). CF strains have been generously provided by Ersilia Fiscarelli (IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy).
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All the procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care Committee of ‘‘G. d’Annunzio’’ University of Chieti-Pescara, and were carried out according to the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institute of Health. This article does not contain any studies with human participants performed by any of the authors.
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Handling Editor: J. D. Wade.
M. Mardirossian and A. Pompilio equally contributed to the work.
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Mardirossian, M., Pompilio, A., Crocetta, V. et al. In vitro and in vivo evaluation of BMAP-derived peptides for the treatment of cystic fibrosis-related pulmonary infections. Amino Acids 48, 2253–2260 (2016). https://doi.org/10.1007/s00726-016-2266-4
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DOI: https://doi.org/10.1007/s00726-016-2266-4