D-BMAP18 Antimicrobial Peptide Is Active In vitro, Resists to Pulmonary Proteases but Loses Its Activity in a Murine Model of Pseudomonas aeruginosa Lung Infection

Abstract

The spread of antibiotic resistant-pathogens is driving the search for new antimicrobial compounds. Pulmonary infections experienced by cystic fibrosis (CF) patients are a dramatic example of this health-care emergency. Antimicrobial peptides could answer the need for new antibiotics but translating them from basic research to the clinic is a challenge. We have previously evaluated the potential of the small membranolytic peptide BMAP-18 to treat CF-related infections, discovering that while this molecule had a good activity <i>in vitro</i> it was not active <i>in vivo</i> because of its rapid degradation by pulmonary proteases. In this study, we synthesized and tested the proteases-resistant all-<i>D</i> enantiomer. In spite of a good antimicrobial activity against <i>Pseudomonas aeruginosa</i> and <i>Stenotrophomonas maltophilia</i> clinical isolates and of a tolerable cytotoxicity <i>in vitro, D</i>-BMAP18 was ineffective to treat <i>P. aeruginosa</i> pulmonary infection in mice, in comparison to tobramycin. We observed that different factors other than peptide degradation hampered its efficacy for pulmonary application. These results indicate that <i>D</i>-BMAP18 needs further optimization before being suitable for clinical application and this approach may represent a guide for optimization of other anti-infective peptides eligible for the treatment of pulmonary infections.