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Issue 6, 2012
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β-Lactam-host defence peptide conjugates as antibiotic prodrug candidates targeting resistant bacteria

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Abstract

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 azidealkyne 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.

Graphical abstract: β-Lactam-host defence peptide conjugates as antibiotic prodrug candidates targeting resistant bacteria

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Publication details

The article was received on 23 Dec 2011, accepted on 04 Jan 2012 and first published on 12 Jan 2012


Article type: Paper
DOI: 10.1039/C2RA01351G
RSC Adv., 2012,2, 2480-2492

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

    S. Desgranges, C. C. Ruddle, L. P. Burke, T. M. McFadden, J. E. O'Brien, D. Fitzgerald-Hughes, H. Humphreys, T. P. Smyth and M. Devocelle, RSC Adv., 2012, 2, 2480
    DOI: 10.1039/C2RA01351G

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