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

2015; American Chemical Society; Volume: 12; Issue: 8 Linguagem: Inglês

10.1021/acs.molpharmaceut.5b00113

1543-8392

Cláudia Monteiro, Marina Pinheiro, Mariana Fernandes, Sílvia Maia, Catarina Leal Seabra, Frederico Ferreira‐da‐Silva, Salette Reis, Paula Gomes, M. Cristina L. Martins,

Biochemical and Structural Characterization

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.