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: Monica Benincasa, Sotir Zahariev, Chiara Pelillo, Annalisa Milan, Renato Gennaro, Marco Scocchi
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 95 Pg. 210-9 (May 05 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 25817771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antimicrobial Cationic Peptides
• Bac7(1-35) peptide
• Polyethylene Glycols

Topics

• Animals
• Antimicrobial Cationic Peptides (chemistry, pharmacokinetics, pharmacology)
• Cell Membrane Permeability (drug effects)
• Humans
• Kidney (drug effects, metabolism)
• Metabolic Clearance Rate
• Mice
• Polyethylene Glycols (chemistry)
• Salmonella Infections, Animal (drug therapy, microbiology)
• Salmonella typhimurium (drug effects)
• Tissue Distribution