In vitro and in vivo evaluation of BMAP-derived peptides for the treatment of cystic fibrosis-related pulmonary infections

• Published in: Amino acids 2016-09, Vol.48 (9), p.2253-2260
• Main Authors: Mardirossian, Mario, Pompilio, Arianna, Crocetta, Valentina, De Nicola, Serena, Guida, Filomena, Degasperi, Margherita, Gennaro, Renato, Di Bonaventura, Giovanni, Scocchi, Marco
• Format: Article
• Language: English
• Subjects: Analytical Chemistry; Animals; Biochemical Engineering; Biochemistry; Biofilms - drug effects; Biofilms - growth & development; Biomedical and Life Sciences; Cystic Fibrosis - drug therapy; Disease Models, Animal; Drug Resistance, Multiple, Bacterial - drug effects; Humans; Life Sciences; Mice; Neurobiology; Original Article; Peptides - chemistry; Peptides - pharmacology; Pneumonia, Staphylococcal - drug therapy; Proteins - chemistry; Proteins - pharmacology; Proteomics; Pseudomonas aeruginosa; Pseudomonas aeruginosa - physiology; Pseudomonas Infections - drug therapy; Staphylococcus aureus; Staphylococcus aureus - physiology; Stenotrophomonas maltophilia
• ISSN: 0939-4451; 1438-2199
• DOI: 10.1007/s00726-016-2266-4

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 MIC 90  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.