Abstract
Pseudomonas aeruginosa is an opportunistic and frequently drug-resistant pulmonary pathogen especially in cystic fibrosis sufferers. Recently, the frog skin-derived antimicrobial peptide (AMP) Esc(1–21) and its diastereomer Esc(1–21)-1c were found to possess potent in vitro antipseudomonal activity. Here, they were first shown to preserve the barrier integrity of airway epithelial cells better than the human AMP LL-37. Furthermore, Esc(1–21)-1c was more efficacious than Esc(1–21) and LL-37 in protecting host from pulmonary bacterial infection after a single intra-tracheal instillation at a very low dosage of 0.1 mg/kg. The protection was evidenced by 2-log reduction of lung bacterial burden and was accompanied by less leukocytes recruitment and attenuated inflammatory response. In addition, the diastereomer was more efficient in reducing the systemic dissemination of bacterial cells. Importantly, in contrast to what reported for other AMPs, the peptide was administered at 2 hours after bacterial challenge to better reflect the real life infectious conditions. To the best of our knowledge, this is also the first study investigating the effect of AMPs on airway-epithelia associated genes upon administration to infected lungs. Overall, our data highly support advanced preclinical studies for the development of Esc(1–21)-1c as an efficacious therapeutic alternative against pulmonary P. aeruginosa infections.
Highlights
Multidrug-resistant (MDR) bacterial infections represent a serious life-threat causing almost 50,000 deaths per year in Europe and in the US; and this number is expected to grow up to tenfold by 2050, killing more than cancer1, 2
Even though antimicrobial peptide (AMP) are under investigation as novel therapeutics to defeat microbial infections, only a few studies have been reported to date on their antibacterial activity in the lungs of animal models of P. aeruginosa pneumonia31, 32
Before performing in vivo studies, the effect of the two esculentin derivatives on the integrity of human airway epithelium was analyzed at three selected peptide concentrations by measuring the transepithelial electrical resistance (TEER) in polarized human primary bronchial cells
Summary
Multidrug-resistant (MDR) bacterial infections represent a serious life-threat causing almost 50,000 deaths per year in Europe and in the US; and this number is expected to grow up to tenfold by 2050, killing more than cancer . We recently identified a short-sized (21 amino acids long) derivative of the frog-skin AMP esculentin-1a, named Esculentin-1a(1–21)NH2 [GIFSKLAGKKIKNLLISGLKG-NH2, Esc[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21]]24, 25, with the following attractive features: (i) a potent and rapid killing kinetics against both planktonic and biofilms forms of P. aeruginosa strains, with a pronounced membrane-perturbing activity as a plausible mode of action26 This is a highly non-specific mechanism which limits the induction of resistance compared to the highly selective conventional antibiotics e.g. tobramycin and ciprofloxacin that would no longer be able to recognize their specific and single target, after mutation; (ii) the ability to preserve antimicrobial activity at high ionic strength, in contrast www.nature.com/scientificreports/. The designed diastereomer demonstrated a higher antibacterial activity than the mammalian AMP LL-37, as well as a comparable potency to that of the clinically used colistin peptide , whose antibacterial activity is exerted through binding to LPS, the major component of the outer membrane of Gram-negative bacteria
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