title: A 17-mer Membrane-Active MSI-78 Derivative with Improved Selectivity toward Bacterial Cells.
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.
authors.affiliation: †I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|‡INEB, Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors.forename: Claudia
authors.initials: C
authors.lastname: Monteiro
authors.affiliation: ∥UCIBIO-REQUIMTE, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors.forename: Marina
authors.initials: M
authors.lastname: Pinheiro
authors.affiliation: †I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|‡INEB, Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Fernandes
authors.affiliation: ⊥UCIBIO-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Maia
authors.affiliation: †I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 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.forename: Catarina L
authors.initials: CL
authors.lastname: Seabra
authors.affiliation: †I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 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.forename: Frederico
authors.initials: F
authors.lastname: Ferreira-da-Silva
authors.affiliation: ∥UCIBIO-REQUIMTE, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors.forename: Salette
authors.initials: S
authors.lastname: Reis
authors.affiliation: ⊥UCIBIO-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
authors.affiliation: †I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 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.
authors.forename: M Cristina L
authors.initials: MC
authors.lastname: Martins
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002942:Circular Dichroism; D004912:Erythrocytes / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013210:Staphylococcus / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; C093828:pexiganan
keywords: MSI-78; antibiotic resistance; antimicrobial peptides; cytotoxicity; membrane models; pexiganan