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Molecular PharmaceuticsVolume 12, Issue 8, 3 August 2015, Pages 2904-2911

A 17-mer Membrane-Active MSI-78 Derivative with Improved Selectivity toward Bacterial Cells(Article)

  • Monteiro, C.,
  • Pinheiro, M.,
  • Fernandes, M.,
  • Maia, S.,
  • Seabra, C.L.,
  • Ferreira-Da-Silva, F.,
  • Reis, S.,
  • Gomes, P.,
  • Martins, M.C.L.
  • View Correspondence (jump link)
  • aI3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
  • bINEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, Porto, 4150-180, Portugal
  • cUCIBIO-REQUIMTE, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
  • dDepartamento de Química e Bioquímica, Faculdade de Cieîncias, Universidade do Porto, Rua do Campo Alegre 687, Porto, 4169-007, Portugal
  • eICBAS-Instituto de Cieîncias Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
  • fIPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Rua Dr. Roberto Frias, Porto, 4200-465, Portugal
  • gIBMC-Instituto de Biologia Celular e Molecular, Unidade de Produção e Purificação de Proteínas, Universidade do Porto, Rua do Campo Alegre 823, Porto, 4150-180, Portugal

Abstract

Antimicrobial peptides are widely recognized as an excellent alternative to conventional antibiotics. MSI-78, a highly effective and broad spectrum AMP, is one of the most promising AMPs for clinical application. In this study, we have designed shorter derivatives of MSI-78 with the aim of improving selectivity while maintaining antimicrobial activity. Shorter 17-mer derivatives were created by truncating MSI-78 at the N- and/or C-termini, while spanning MSI-78 sequence. Despite the truncations made, we found a 17-mer peptide, MSI-78(4-20) (KFLKKAKKFGKAFVKIL), which was demonstrated to be as effective as MSI-78 against the Gram-positive Staphylococcus strains tested and the Gram-negative Pseudomonas aeruginosa. This shorter derivative is more selective toward bacterial cells as it was less toxic to erythrocytes than MSI-78, representing an improved version of the lead peptide. Biophysical studies support a mechanism of action for MSI-78(4-20) based on the disruption of the bacterial membrane permeability barrier, which in turn leads to loss of membrane integrity and ultimately to cell death. These features point to a mechanism of action similar to the one described for the lead peptide MSI-78. © 2015 American Chemical Society.

Author keywords

antibiotic resistanceantimicrobial peptidescytotoxicitymembrane modelsMSI-78pexiganan

Indexed keywords

EMTREE drug terms:pexigananpexiganan derivativeunclassified drugantiinfective agentantimicrobial cationic peptidepexiganan
EMTREE medical terms:amino terminal sequenceantimicrobial activityArticlebacterial cellbacterial membranebacterial straincarboxy terminal sequencecell deathcircular dichroismcontrolled studydrug conformationdrug cytotoxicitydrug selectivityerythrocytehemolysishumanhuman cellhydrodynamicshydrophobicitymethicillin resistant Staphylococcus aureusminimum bactericidal concentrationminimum inhibitory concentrationnonhumanpermeability barrierphysical chemistrypriority journalprotein secondary structurePseudomonas aeruginosaStaphylococcus aureuszeta potentialcell membranecell membrane permeabilitychemistrydrug effectsmetabolismmicrobial sensitivity testStaphylococcus
MeSH:Anti-Infective AgentsAntimicrobial Cationic PeptidesCell MembraneCell Membrane PermeabilityCircular DichroismErythrocytesHumansMicrobial Sensitivity TestsPseudomonas aeruginosaStaphylococcus

Chemicals and CAS Registry Numbers:

pexiganan, 172820-23-4, 147664-63-9;

Anti-Infective Agents; Antimicrobial Cationic Peptides; pexiganan

Drug tradename:

  • msi 78

Funding details

Funding sponsor Funding number Acronym
Federación Española de Enfermedades RarasFEDER
Sakarya ÜniversitesiLA0002/2013SAU
  • ISSN: 15438384
  • CODEN: MPOHB
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1021/acs.molpharmaceut.5b00113
  • PubMed ID: 26066462
  • Document Type: Article
  • Publisher: American Chemical Society

  Martins, M.C.L.; INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, Porto, Portugal;
© Copyright 2016 Elsevier B.V., All rights reserved.

Cited by 6 documents

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