The Anti-Pseudomonal Peptide D-BMAP18 Is Active in Cystic Fibrosis Sputum and Displays Anti-Inflammatory In Vitro Activity.

Margherita Degasperi,Chiara Agostinis,Marco Scocchi,Mario Mardirossian,Andrea Taddio,Roberta Bulla,Massimo Maschio

doi:10.3390/microorganisms8091407

Margherita Degasperi, Chiara Agostinis + Show 5 more

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https://doi.org/10.3390/microorganisms8091407

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Abstract

Most Cystic Fibrosis (CF) patients succumb to airway inflammation and pulmonary infections due to Pseudomonas aeruginosa. D-BMAP18, a membrane-permeabilizing antimicrobial peptide composed of D-amino acids, was evaluated as a possible antibacterial aimed to address this issue. The antipseudomonal activity of D-BMAP18 was tested in a pathophysiological context. The peptide displayed activity against CF isolates of Pseudomonas aeruginosa in the presence of CF sputum when combined with sodium chloride and DNase I. In combination with DNase I, D-BMAP18 discouraged the deposition of new biofilm and eradicated preformed biofilms of some P. aeruginosa strains. In addition, D-BMAP18 down regulated the production of TNF-α, IL1-β, and TGF-β in LPS-stimulated or IFN-γ macrophages derived from THP-1 cells indicating an anti-inflammatory activity. The biocompatibility of D-BMAP18 was assessed using four different cell lines, showing that residual cell-specific cytotoxicity at bactericidal concentrations could be abolished by the presence of CF sputum. Overall, this study suggests that D-BMAP18 may be an interesting molecule as a starting point to develop a novel therapeutic agent to simultaneously contrast lung infections and inflammation in CF patients.

Highlights

Lung diseases are the main cause of mortality in cystic fibrosis (CF)
The anti-pseudomonal activity of D-BMAP18 was evaluated in CF sputum; we successively analyzed its anti-biofilm function against P. aeruginosa strains and in order to investigate possible synergisms, we evaluated the antimicrobial activity of D-BMAP18 in co-administration with compounds already approved for CF treatment
The killing activity of D-BMAP18 against P. aeruginosa was evaluated in SCFM medium and in 25% CF sputum diluted in SCFM medium to assess peptide activity in conditions mimicking the in vivo environment

Summary

Introduction

Lung diseases are the main cause of mortality in cystic fibrosis (CF). Most CF patients succumb to respiratory failure brought on by chronic bacterial infection and airway chronic inflammation [1,2,3,4]. Intensive antibiotic therapy is required to maintain lung function and to eradicate bacterial pathogens, but nowadays the anti-infective treatment has to face the emergence of multidrug-resistant (MDR) pathogen strains [6,7,8]. This problem is worsened by the adaptation of pathogens to the CF pulmonary environment, and by the formation of biofilms [9]. AMPs are naturally part of the innate immune system They have important roles in the host’s defense, showing broad activity spectrum and a slow rate of acquired resistance by pathogens [12]

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