Clinical Microbiology and Infection
Clinical Microbiology and Infection
5 years ago

Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of P. aeruginosa pneumonia

Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of P. aeruginosa pneumonia
P. aeruginosa is a common cause of pneumonia in cystic fibrosis patients with the property to generate multidrug resistance against clinically used antibiotics. Antimicrobial peptides (AMPs) are a diverse group of effector molecules of the innate immunity that protect the host against pathogens. However, the lack of activity in common biological matrices has hampered efforts towards clinical development. In this study, we evaluated the therapeutic potential of engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of P. aeruginosa infection. Methods The human AMP LL37 and WLBU2 were compared for (1) antibiofilm activity using P. aeruginosa on polarized human bronchial epithelial cells; (2) efficacy in P. aeruginosa pneumonia in mice using intra-tracheal (i.t.) instillation of bacteria and AMPs. Results WLBU2 (16μM) prevents biofilm formation by up to 3-log compared to 1-log reduction by LL37. With a single dose of 1μg (0.05mg/kg) delivered i.t., the initial effect of LL37 was moderate and transitory, as bacterial load and inflammatory cytokines increased at 24h with observed signs of disease such as lethargy and hypothermia (L&H), consistent with moribund state requiring euthanasia. In sharp contrast, WLBU2 reduced bacterial burden (by 2 logs) and bacteria-induced inflammation (leucocytic infiltrates, cytokine and chemokine gene expression) at 6h and 24h post-exposure, with no observed signs of disease or host toxicity. Conclusion These promising results now establish a much lower minimum therapeutic dose (mTd) of WLBU2 (a net gain of 80-fold) compared to the previously reported 4mg/kg systemic mTd, with significant implications for clinical development.

Publisher URL: www.sciencedirect.com/science

DOI: S1198743X17304925

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