β-Lactam-host defence peptide conjugates as antibioticprodrug candidates targeting resistant bacteria

Authors: Desgranges, Stephane; Ruddle, Carol C.; Burke, Liam P.; McFadden, Tara M.; O'Brien, John E.; Fitzgerald-Hughes, Deirdre; Humphreys, Hilary; Smyth, Timothy P.; Devocelle, Marc; RSC Advances; (2012); 10.1039/c2ra01351g

The first hybrid molecule of a β-lactam antibiotic and a host defence peptide and a method for the preparation of this type of molecule are reported. Conjugation of an antimicrobial peptide to a cephalosporin, through a cleavable linker, reversibly masks one of the activity determinants of the peptide. Its release from the β-lactam core can be selectively triggered by bacterial enzymes (β-lactamases) which mediate resistance to β-lactam agents. A prototypical cephalothin-bactenecin candidate was synthesised, using a copper(I)-catalysed azide–alkyne cyclo-addition reaction for the conjugation step. Enzymatic hydrolysis assays of this candidate were initially performed with a purified β-lactamase to confirm that the peptide can be released from the cephalosporin. The antimicrobial activity of the conjugate was then assessed against representative strains of bacteria and compared to the activities of its parent β-lactam and peptide components and to those of two analogous conjugates based on non-cleavable linkers. The results of these assays indicate that the conjugate has an activity distinct from its separate constituents and that the release of the peptide from the cephalosporin may contribute to its mechanism of action. Furthermore, the results of antimicrobial assays performed with an isogenic strain of bacteria expressing or not an extended-spectrum β-lactamase, suggest that antimicrobial peptide prodrug candidates targeting resistant bacteria could be generated from these hybrid antibiotics.