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De novo identification of lipid II binding lipopeptides with antibacterial activity against vancomycin-resistant bacteria

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Abstract

Creative strategies for identifying new antibiotics are essential to addressing the looming threat of a post-antibiotic era. We here report the use of a targeted peptide phage display screen as a means of generating novel antimicrobial lipopeptides. Specifically, a library of phage displayed bicyclic peptides was screened against a biomolecular target based on the bacterial cell wall precursor lipid II. In doing so we identified unique lipid II binding peptides that upon lipidation were found to be active against a range of Gram-positive bacteria including clinically relevant strains of vancomycin resistant bacteria. Optimization of the peptide sequence led to variants with enhanced antibacterial activity and reduced hemolytic activity. Biochemical experiments further confirm a lipid II mediated mode of action for these new-to-nature antibacterial lipopeptides.

Graphical abstract: De novo identification of lipid II binding lipopeptides with antibacterial activity against vancomycin-resistant bacteria

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Publication details

The article was received on 04 Aug 2017, accepted on 29 Sep 2017 and first published on 02 Oct 2017


Article type: Edge Article
DOI: 10.1039/C7SC03413J
Citation: Chem. Sci., 2017, Advance Article
  • Open access: Creative Commons BY license
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    De novo identification of lipid II binding lipopeptides with antibacterial activity against vancomycin-resistant bacteria

    P. 't Hart, T. M. Wood, K. H. M. E. Tehrani, R. M. van Harten, M. Śleszyńska, I. Rentero Rebollo, A. P. A. Hendrickx, R. J. L. Willems, E. Breukink and N. I. Martin, Chem. Sci., 2017, Advance Article , DOI: 10.1039/C7SC03413J

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