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Antimicrobial properties of analgesic kyotorphin peptides unraveled through atomic force microscopy

Antimicrobial peptides (AMPs) are promising candidates as alternatives to conventional antibiotics for the treatment of resistant pathogens. In the last decades, new AMPs have been found from the cleavage of intact proteins with no antibacterial activity themselves. Bovine hemoglobin hydrolysis, for instance, results in AMPs and the minimal antimicrobial peptide sequence was defined as Tyr-Arg plus a positively charged amino acid residue. The Tyr-Arg dipeptide alone, known as kyotorphin (KTP), is an endogenous analgesic neuropeptide but has no antimicrobial activity itself. In previous studies new KTP derivatives combining C-terminal amidation and Ibuprofen (Ib) - KTP-NH 2, IbKTP, IbKTP-NH 2 - were designed in order to improve KTP brain targeting. Those modifications succeeded in enhancing peptide-cell membrane affinity towards fluid anionic lipids and higher analgesic activity after systemic injection resulted therefrom. Here, we investigated if this affinity for anionic lipid membranes also translates into antimicrobial activity because bacteria have anionic membranes. Atomic force microscopy revealed that KTP derivatives perturbed Staphylococcus aureus membrane structure by inducing membrane blebbing, disruption and lysis. In addition, these peptides bind to red blood cells but are non-hemolytic. From the KTP derivatives tested, amidated KTP proves to be the most active antibacterial agent. The combination of analgesia and antibacterial activities with absence of toxicity is highly appealing from the clinical point of view and broadens the therapeutic potential and application of kyotorphin peptides

Unidade de Microbiologia Molecular e Infeccao from Instituto de Medicina Molecular are acknowledged for the kind gift of E. coli and S. aureus strains. Dr. Sonia T. Henriques is acknowledged for helpful discussions. Fundacao para a Ciencia e Tecnologia (Portugal) is acknowledged for funding (SFRH/BD/42158/2007 fellowship to M.M.B.R. and SFRH/BD/39039/2007 fellowship to H.G.F.). Marie Curie Industry-Academia Partnerships and Pathways (European Commission) is also acknowledged for funding and fellowship to V. G. R. (FP7-PEOPLE-2007-3-1-IAPP, Project 230654)

© Biochemical and Biophysical Research Communications, 2012, vol. 420, p. 676-679

Elsevier

Author: Ribeiro, Marta M B
Franquelim, Henri G.
Torcato, Inês M.
Ramu, Vasanthakumar Ganga
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Castanho, Miguel Augusto Rico Botas
Date: 2012 April 13
Abstract: Antimicrobial peptides (AMPs) are promising candidates as alternatives to conventional antibiotics for the treatment of resistant pathogens. In the last decades, new AMPs have been found from the cleavage of intact proteins with no antibacterial activity themselves. Bovine hemoglobin hydrolysis, for instance, results in AMPs and the minimal antimicrobial peptide sequence was defined as Tyr-Arg plus a positively charged amino acid residue. The Tyr-Arg dipeptide alone, known as kyotorphin (KTP), is an endogenous analgesic neuropeptide but has no antimicrobial activity itself. In previous studies new KTP derivatives combining C-terminal amidation and Ibuprofen (Ib) - KTP-NH 2, IbKTP, IbKTP-NH 2 - were designed in order to improve KTP brain targeting. Those modifications succeeded in enhancing peptide-cell membrane affinity towards fluid anionic lipids and higher analgesic activity after systemic injection resulted therefrom. Here, we investigated if this affinity for anionic lipid membranes also translates into antimicrobial activity because bacteria have anionic membranes. Atomic force microscopy revealed that KTP derivatives perturbed Staphylococcus aureus membrane structure by inducing membrane blebbing, disruption and lysis. In addition, these peptides bind to red blood cells but are non-hemolytic. From the KTP derivatives tested, amidated KTP proves to be the most active antibacterial agent. The combination of analgesia and antibacterial activities with absence of toxicity is highly appealing from the clinical point of view and broadens the therapeutic potential and application of kyotorphin peptides
Unidade de Microbiologia Molecular e Infeccao from Instituto de Medicina Molecular are acknowledged for the kind gift of E. coli and S. aureus strains. Dr. Sonia T. Henriques is acknowledged for helpful discussions. Fundacao para a Ciencia e Tecnologia (Portugal) is acknowledged for funding (SFRH/BD/42158/2007 fellowship to M.M.B.R. and SFRH/BD/39039/2007 fellowship to H.G.F.). Marie Curie Industry-Academia Partnerships and Pathways (European Commission) is also acknowledged for funding and fellowship to V. G. R. (FP7-PEOPLE-2007-3-1-IAPP, Project 230654)
Format: application/pdf
ISSN: 0006-291X
Document access: http://hdl.handle.net/10256/10173
Language: eng
Publisher: Elsevier
Collection: Reproducció digital del document publicat a: http://dx.doi.org/10.1016/j.bbrc.2012.03.065
Articles publicats (D-Q)
info:eu-repo/grantAgreement/EC/FP7/230654
Is part of: © Biochemical and Biophysical Research Communications, 2012, vol. 420, p. 676-679
Rights: Tots els drets reservats
Subject: Analgèsics
Analgesics
Antibiòtics pèptids
Peptide antibiotics
Microscòpia de força atòmica
Atomic force microscopy
Title: Antimicrobial properties of analgesic kyotorphin peptides unraveled through atomic force microscopy
Type: info:eu-repo/semantics/article
Repository: DUGiDocs

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