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Anti-microbial activity, Antimicrobial peptide, Bacterial enzymes, Hybrid antibiotic, Hybrid molecules, Isogenic strain, Lactamases, Mechanism of action, Prodrugs, Representative strain, Resistant bacteria.


This publication has emanated from research conducted with the financial support of Science Foundation Ireland (SFI 05/RFP/ CHE0063 and 06/RFP/CHO024/EC07), Enterprise Ireland (EI PC/2005/164) and the Health Research Board (HRB PHD/2007/ 11).


The original article is available at!divAbstract


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 conjugationstep. 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.


Medicine and Health Sciences


Desgranges S, Ruddle CC, Burke LP, McFadden TM, O'Brien JE, Fitzgerald-Hughes D, Humphreys H, Timothy P. Smyth TP, Devocelle M. β-Lactam-host defence peptide conjugates as antibiotic prodrug candidates targeting resistant bacteria. 2012;(2):2480-2492.

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