title: Antimicrobial properties of membrane-active dodecapeptides derived from MSI-78.
abstract: Antimicrobial peptides (AMPs) are a class of broad-spectrum antibiotics known by their ability to disrupt bacterial membranes and their low tendency to induce bacterial resistance, arising as excellent candidates to fight bacterial infections. In this study we aimed at designing short 12-mer AMPs, derived from a highly effective and broad spectrum synthetic AMP, MSI-78 (22 residues), by truncating this peptide at the N- and/or C-termini while spanning its entire sequence with 1 amino acid (aa) shifts. These designed peptides were evaluated regarding antimicrobial activity against selected gram-positive Staphylococcus strains and the gram-negative Pseudomonas aeruginosa (P. aeruginosa). The short 12-mer peptide CEM1 (GIGKFLKKAKKF) was identified as an excellent candidate to fight P. aeruginosa infections as it displays antimicrobial activity against this strain and selectivity, with negligible toxicity to mammalian cells even at high concentrations. However, in general most of the short 12-mer peptides tested showed a reduction in antimicrobial activity, an effect that was more pronounced for gram-positive Staphylococcus strains. Interestingly, CEM1 and a highly similar peptide differing by only one aa-shift (CEM2: IGKFLKKAKKFG), showed a remarkably contrasting AMP activity. These two peptides were chosen for a more detailed study regarding their mechanism of action, using several biophysical assays and simple membrane models that mimic the mammalian and bacterial lipid composition. We confirmed the correlation between peptide helicity and antimicrobial activity and propose a mechanism of action based on the disruption of the bacterial membrane permeability barrier.
authors: I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors: Claudia
authors: C
authors: Monteiro
authors: I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors: Mariana
authors: M
authors: Fernandes
authors: Requimte, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors: Marina
authors: M
authors: Pinheiro
authors: CIQUP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors: Sílvia
authors: S
authors: Maia
authors: I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal.
authors: Catarina L
authors: CL
authors: Seabra
authors: I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; IBMC - Instituto de Biologia Celular e Molecular, Unidade de Produção e Purificação de Proteínas, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors: Frederico
authors: F
authors: Ferreira-da-Silva
authors: I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal; Faculdade de Engenharia, Universidade do Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal.
authors: Fabíola
authors: F
authors: Costa
authors: Requimte, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors: Salette
authors: S
authors: Reis
authors: CIQUP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors: Paula
authors: P
authors: Gomes
authors: I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. Electronic address: cmartins@ineb.up.pt.
authors: M Cristina L
authors: MC
authors: Martins
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002462:Cell Membrane / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004910:Erythrocyte Membrane / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry; D008567:Membranes, Artificial; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D008563:Membrane Lipids; D008567:Membranes, Artificial; D009842:Oligopeptides; D010446:Peptide Fragments; C093828:pexiganan
keywords: Antibiotic resistance; Antimicrobial peptide; Cytotoxicity; MSI-78; Membrane model; Pexiganan