title: PEGylation of the peptide Bac7(1-35) reduces renal clearance while retaining antibacterial activity and bacterial cell penetration capacity.
abstract: The proline-rich antibacterial peptide Bac7(1-35) protects mice against Salmonella typhimurium infection, despite its rapid clearance. To overcome this problem the peptide was linked to a polyethylene glycol (PEG) molecule either via a cleavable ester bond or via a non-hydrolysable amide bond. Both the PEGylated conjugates retained most of the in vitro activity against S. typhimurium. In addition, the ester bond was cleaved in human serum or plasma, releasing a carboxymethyl derivative of Bac7(1-35) which accounts for a higher activity of this peptide with relative to the other, non-hydrolysable form. Both PEGylated peptides maintained the capacity of the unconjugated form to kill bacteria without permeabilizing the bacterial membranes, by penetrating into cells. They exploited the same transporter as unmodified Bac7(1-35), suggesting it has the capacity to internalize quite sizeable cargo if this is linked to Bac7 fragment. PEGylation allows the peptide to have a wide distribution in mice, and a slow renal clearance, indicating that this strategy would improve the bioavailability of Bac7, and in principle of other antimicrobial peptides. This can be an equally important issue to reducing cytotoxicity for therapeutic use of these antibacterials.
authors.affiliation: Department of Life Sciences, University of Trieste, Via Giorgieri 5, 34127 Trieste, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Benincasa
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors.forename: Sotir
authors.initials: S
authors.lastname: Zahariev
authors.affiliation: Department of Life Sciences, University of Trieste, Via Giorgieri 5, 34127 Trieste, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pelillo
authors.affiliation: Department of Life Sciences, University of Trieste, Via Giorgieri 5, 34127 Trieste, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Milan
authors.affiliation: Department of Life Sciences, University of Trieste, Via Giorgieri 5, 34127 Trieste, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Gennaro
authors.affiliation: Department of Life Sciences, University of Trieste, Via Giorgieri 5, 34127 Trieste, Italy. Electronic address: mscocchi@units.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Scocchi
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D012481:Salmonella Infections, Animal / Q000188:drug therapy* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000187:drug effects*; D014018:Tissue Distribution
chemical_list: D023181:Antimicrobial Cationic Peptides; C481640:Bac7(1-35) peptide; D011092:Polyethylene Glycols
keywords: Antibacterial activity; Antimicrobial peptide; Cell penetrating; Optical imaging; PEGylation; Proline-rich