title: Rational modification of a dendrimeric peptide with antimicrobial activity: consequences on membrane-binding and biological properties.
abstract: Peptide-based antibiotics might help containing the rising tide of antimicrobial resistance. We developed SB056, a semi-synthetic peptide with a dimeric dendrimer scaffold, active against both Gram-negative and Gram-positive bacteria. Being the mechanism of SB056 attributed to disruption of bacterial membranes, we enhanced the amphiphilic profile of the original, empirically derived sequence [WKKIRVRLSA-NH2] by interchanging the first two residues [KWKIRVRLSA-NH2], and explored the effects of this modification on the interaction of peptide, both in linear and dimeric forms, with model membranes and on antimicrobial activity. Results obtained against Escherichia coli and Staphylococcus aureus planktonic strains, with or without salts at physiological concentrations, confirmed the added value of dendrimeric structure over the linear one, especially at physiological ionic strength, and the impact of the higher amphipathicity obtained through sequence modification on enhancing peptide performances. SB056 peptides also displayed intriguing antibiofilm properties. Staphylococcus epidermidis was the most susceptible strain in sessile form, notably to optimized linear analog lin-SB056-1 and the wild-type dendrimer den-SB056. Membrane affinity of all peptides increased with the percentage of negatively charged lipids and was less influenced by the presence of salt in the case of dendrimeric peptides. The analog lin-SB056-1 displayed the highest overall affinity, even for zwitterionic PC bilayers. Thus, in addition to electrostatics, distribution of charged/polar and hydrophobic residues along the sequence might have a significant role in driving peptide-lipid interaction. Supporting this view, dendrimeric analog den-SB056-1 retained greater membrane affinity in the presence of salt than den-SB056, despite the fact that they bear exactly the same net positive charge.
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Batoni
authors.affiliation: Department of Chemical and Geological Sciences, University of Cagliari, Cittadella Universitaria, Monserrato (CA), Italy.
authors.forename: Mariano
authors.initials: M
authors.lastname: Casu
authors.affiliation: Research and Development Unit, Spider Biotech S.r.l., Colleretto Giacosa (TO), Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giuliani
authors.affiliation: Dipartimento di Scienze Biochimiche, "A. Rossi Fanelli", Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Luca
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Giuseppantonio
authors.initials: G
authors.lastname: Maisetta
authors.affiliation: Dipartimento di Scienze Biochimiche, "A. Rossi Fanelli", Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Rome, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Mangoni
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato (CA), Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Manzo
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato (CA), Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pintus
authors.affiliation: Research and Development Unit, Spider Biotech S.r.l., Colleretto Giacosa (TO), Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pirri
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato (CA), Italy. rinaldi@unica.it.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Rinaldi
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato (CA), Italy.
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Scorciapino
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato (CA), Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Serra
authors.affiliation: Institute of Biological Interfaces (IBG-2), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.|Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Ulrich
authors.affiliation: Institute of Biological Interfaces (IBG-2), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Parvesh
authors.initials: P
authors.lastname: Wadhwani
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides
keywords: Antimicrobial peptides; Biofilms; Dendrimers; Gram-negative; Gram-positive; Model membranes