title: A novel dendrimeric peptide with antimicrobial properties: structure-function analysis of SB056.
abstract: The novel antimicrobial peptide with a dimeric dendrimer scaffold, SB056, was empirically optimized by high-throughput screening. This procedure produced an intriguing primary sequence whose structure-function analysis is described here. The alternating pattern of hydrophilic and hydrophobic amino acids suggests the possibility that SB056 is a membrane-active peptide that forms amphiphilic β-strands in a lipid environment. Circular dichroism confirmed that the cationic SB056 folds as β-sheets in the presence of anionic vesicles. Lipid monolayer surface pressure experiments revealed unusual kinetics of monolayer penetration, which suggest lipid-induced aggregation as a membranolytic mechanism. NMR analyses of the linear monomer and the dendrimeric SB056 in water and in 30% trifluoroethanol, on the other hand, yielded essentially unstructured conformations, supporting the excellent solubility and storage properties of this compound. However, simulated annealing showed that many residues lie in the β-region of the Ramachandran plot, and molecular-dynamics simulations confirmed the propensity of this peptide to fold as a β-type conformation. The excellent solubility in water and the lipid-induced oligomerization characteristics of this peptide thus shed light on its mechanism of antimicrobial action, which may also be relevant for systems that can form toxic β-amyloid fibrils when in contact with cellular membranes. Functionally, SB056 showed high activity against Gram-negative bacteria and some limited activity against Gram-positive bacteria. Its potency against Gram-negative strains was comparable (on a molar basis) to that of colistin and polymyxin B, with an even broader spectrum of activity than numerous other reference compounds.
authors.affiliation: Department of Chemical Sciences, Istituto Officina dei Materiali del Consiglio Nazionale delle Ricerche, UOS SLACS, Italy.
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Scorciapino
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pirri
authors.forename: Attilio V
authors.initials: AV
authors.lastname: Vargiu
authors.forename: Paolo
authors.initials: P
authors.lastname: Ruggerone
authors.forename: Andrea
authors.initials: A
authors.lastname: Giuliani
authors.forename: Mariano
authors.initials: M
authors.lastname: Casu
authors.forename: Jochen
authors.initials: J
authors.lastname: Buerck
authors.forename: Parvesh
authors.initials: P
authors.lastname: Wadhwani
authors.forename: Anne S
authors.initials: AS
authors.lastname: Ulrich
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Rinaldi
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D019281:Dimerization; D057927:Hydrophobic and Hydrophilic Interactions; D008563:Membrane Lipids / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D023181:Antimicrobial Cationic Peptides; D050091:Dendrimers; D008563:Membrane Lipids