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Chemical space guided discovery of antimicrobial bridged bicyclic peptides against Pseudomonas aeruginosa and its biofilms

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Abstract

Herein we report the discovery of antimicrobial bridged bicyclic peptides (AMBPs) active against Pseudomonas aeruginosa, a highly problematic Gram negative bacterium in the hospital environment. Two of these AMBPs show strong biofilm inhibition and dispersal activity and enhance the activity of polymyxin, currently a last resort antibiotic against which resistance is emerging. To discover our AMBPs we used the concept of chemical space, which is well known in the area of small molecule drug discovery, to define a small number of test compounds for synthesis and experimental evaluation. Our chemical space was calculated using 2DP, a new topological shape and pharmacophore fingerprint for peptides. This method provides a general strategy to search for bioactive peptides with unusual topologies and expand the structural diversity of peptide-based drugs.

Graphical abstract: Chemical space guided discovery of antimicrobial bridged bicyclic peptides against Pseudomonas aeruginosa and its biofilms

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Publication details

The article was received on 23 Mar 2017, accepted on 12 Jul 2017 and first published on 13 Jul 2017


Article type: Edge Article
DOI: 10.1039/C7SC01314K
Citation: Chem. Sci., 2017, Advance Article
  • Open access: Creative Commons BY-NC license
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    Chemical space guided discovery of antimicrobial bridged bicyclic peptides against Pseudomonas aeruginosa and its biofilms

    I. Di Bonaventura, X. Jin, R. Visini, D. Probst, S. Javor, B. Gan, G. Michaud, A. Natalello, S. M. Doglia, T. Köhler, C. van Delden, A. Stocker, T. Darbre and J. Reymond, Chem. Sci., 2017, Advance Article , DOI: 10.1039/C7SC01314K

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