D-Amino acids incorporation in the frog skin-derived peptide esculentin-1a(1-21)NH2 is beneficial for its multiple functions

Antonio Di Grazia, Floriana Cappiello, Hadar Cohen, Bruno Casciaro, Vincenzo Luca, Alessandro Pini, Y. Peter Di, Yechiel Shai, Maria Luisa Mangoni

Research output: Contribution to journalArticlepeer-review

Abstract

Naturally occurring antimicrobial peptides (AMPs) represent promising future antibiotics. We have previously isolated esculentin-1a(1-21)NH2, a short peptide derived from the frog skin AMP esculentin-1a, with a potent anti-Pseudomonal activity. Here, we investigated additional functions of the peptide and properties responsible for these activities. For that purpose, we synthesized the peptide, as well as its structurally altered analog containing two d-amino acids. The peptides were then biophysically and biologically investigated for their cytotoxicity and immunomodulating activities. The data revealed that compared to the wild-type, the diastereomer: (1) is significantly less toxic towards mammalian cells, in agreement with its lower α-helical structure, as determined by circular dichroism spectroscopy; (2) is more effective against the biofilm form of Pseudomonas aeruginosa (responsible for lung infections in cystic fibrosis sufferers), while maintaining a high activity against the free-living form of this important pathogen; (3) is more stable in serum; (4) has a higher activity in promoting migration of lung epithelial cells, and presumably in healing damaged lung tissue, and (5) disaggregates and detoxifies the bacterial lipopolysaccharide (LPS), albeit less than the wild-type. Light scattering studies revealed a correlation between anti-LPS activity and the ability to disaggregate the LPS. Besides shedding light on the multifunction properties of esculentin-1a(1-21)NH2, the d-amino acid containing isomer may serve as an attractive template for the development of new anti-Pseudomonal compounds with additional beneficial properties. Furthermore, together with other studies, incorporation of d-amino acids may serve as a general approach to optimize the future design of new AMPs.

Original languageEnglish
Pages (from-to)2505-2519
Number of pages15
JournalAmino Acids
Volume47
Issue number12
DOIs
StatePublished - 1 Dec 2015
Externally publishedYes

Keywords

  • Anti-biofilm activity
  • Antimicrobial peptide
  • Diastereomer
  • Esculentin-1
  • Wound healing

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