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Amino Acids

, Volume 47, Issue 12, pp 2505–2519 | Cite as

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 MangoniEmail author
Original Article

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.

Keywords

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

Abbreviations

AMP

Antimicrobial peptide

CD

Circular dichroism

CFU

Colony-forming units

DMEMg

Dulbecco’s modified Eagle’s medium supplemented with glutamine

FBS

Heat-inactivated fetal bovine serum

LB

Luria–Bertani broth

LPC

Lysophosphatidylcholine

LPS

Lipopolysaccharide

MTT

3(4,5-Dimethylthiazol-2yl)2,5-diphenyltetrazolium bromide

PBS

Phosphate buffered saline

Notes

Acknowledgments

The authors thank Silvia Scali (University of Siena, Italy) for the help in the peptides stability studies as well as Dr. Alessandra Bragonzi (San Raffaele Institute, Milan, Italy) and Professor Burkhard Tummler (Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany) for the P. aeruginosa clinical isolates. This work was supported by grants from Sapienza Università di Roma and the Italian Foundation for Cystic Fibrosis (Project FFC#11/2014 adopted by FFC Delegations from Siena, Sondrio Valchiavenna, Cerea Il Sorriso di Jenny and Pavia). The Ordine Nazionale dei Biologi is acknowledged for the fellowship provided to V.L. Y. Shai is incumbents of The Harold S. and Harriet B. Brady Professorial Chair in Cancer Research. Part of the content of this work is object of a US patent application N. 14/506,383.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Antonio Di Grazia
    • 1
  • Floriana Cappiello
    • 1
  • Hadar Cohen
    • 2
  • Bruno Casciaro
    • 1
  • Vincenzo Luca
    • 1
  • Alessandro Pini
    • 3
  • Y. Peter Di
    • 4
  • Yechiel Shai
    • 2
  • Maria Luisa Mangoni
    • 1
    Email author
  1. 1.Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biochemical SciencesSapienza University of RomeRomeItaly
  2. 2.Department of Biological ChemistryThe Weizmann Institute of ScienceRehovotIsrael
  3. 3.Department of Medical BiotechnologyUniversity of SienaSienaItaly
  4. 4.Department of Environmental and Occupational HealthUniversity of PittsburghPittsburghUSA

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