Toward optimization of antimicrobial peptides for the treatment of multidrug resistant infections in cystic fibrosis.

Patients with cystic fibrosis (CF) often require pharmacological treatment against problematic chronic lung infections due to antibiotic-resistant strains. A strategy to overcome this concern may be the use of Antimicrobial Peptides (AMPs). Although several AMPs are active in vitro against resistant strains and can eradicate or counteract the formation of biofilms, they often show acute toxicity when administrated in vivo. Our aim was to develop some modified forms of natural cathelicidins, in order to retain a good bactericidal activity while reducing the effects of toxicity toward the host. BMAP-27 (1-18), BMAP28 (1-18) and mBMAP28 have been synthesized and their activity against 45 CF strains (15 each of P. aeruginosa, S. aureus, and S. maltophilia) was assessed. The acute toxicity at pulmonary level of AMPs was also evaluated in a mouse model following intratracheal instillation. All AMPs have shown to maintain a good antibacterial activity in vitro, when compared to the natural molecules. Toxicity assays in vivo showed that BMAP-27 (1-18) was the less toxic among the tested peptides. Brought together, results from antimicrobial activity and lung toxicity showed BMAP-27 (1-18) as the best peptide to be tested for in vivo activity in a murine model of acute lung infection by P. aeruginosa. In spite of promising in vitro antibacterial activity, BMAP-27 (1-18) did not show the desired curative effect in vivo. These results indicate that further studies are necessary on the route of administration, and to reduce the toxicity in order to optimize BMAP-27 (1-18) for the pulmonary environment.