Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

Steven M. Wales; Katherine A. Hammer; Amy M. King; Andrew J. Tague; Dena Lyras; Thomas V. Riley; Paul A. Keller; Stephen G. Pyne

doi:10.1039/c5ob00576k

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Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

Journal article

Peer reviewed

Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

Steven M. Wales, Katherine A. Hammer, Amy M. King, Andrew J. Tague, Dena Lyras, Thomas V. Riley, Paul A. Keller and Stephen G. Pyne

Organic & Biomolecular Chemistry, Vol.13(20), pp.5743-5756

2015

DOI: https://doi.org/10.1039/c5ob00576k

PMID: 25901416

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Abstract

Clostridium difficile (C. difficile) is a problematic Gram positive bacterial pathogen causing moderate to severe gastrointestinal infections. Based on a lead binaphthyl-tripeptide dicationic antimicrobial, novel mono-, di- and tri-peptidomimetic analogues targeting C. difficile were designed and synthesized incorporating one, two or three D-configured cationic amino acid residues, with a common 1,2,3-triazole ester isostere at the C-terminus. Copper-and ruthenium-click chemistry facilitated the generation of a 46 compound library for in vitro bioactivity assays, with structure-activity trends over the largest compound subset revealing a clear advantage to triazole-substitution with a linear or branched hydrophobic group. The most active compounds were dicationic-dipeptides where the triazole was substituted with a 4- or 5-cyclohexylmethyl or 4,5-diphenyl moiety, providing MICs of 4 mu g mL(-1) against three human isolates of C. difficile. Further biological screening revealed significant antimicrobial activity for several compounds against other common bacterial pathogens, both Gram positive and negative, including S. aureus (MICs >= 2 mu g mL(-1)), S. pneumoniae (MICs >= 1 mu g mL(-1)), E. coli (MICs >= 4 mu g mL(-1)), A. baumannii (MICs >= 4 mu g mL(-1)) and vancomycin-resistant E. faecalis (MICs >= 4 mu g mL(-1)).

Details

Title: Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria
Authors: Steven M. Wales (Author) - University of Wollongong
Katherine A. Hammer (Author) - University of Western Australia
Amy M. King (Author) - Monash University
Andrew J. Tague (Author) - University of Wollongong
Dena Lyras (Author) - Monash University
Thomas V. Riley (Author) - University of Western Australia
Paul A. Keller (Corresponding Author) - University of Wollongong
Stephen G. Pyne (Corresponding Author) - University of Wollongong
Publication details: Organic & Biomolecular Chemistry, Vol.13(20), pp.5743-5756
Publisher: Royal Society of Chemistry
DOI: 10.1039/c5ob00576k
ISSN: 1477-0539
PMID: 25901416
Grant note: Australian Research Council (ARC) Australian National Health and Medical Research Council (NHMRC)
Organisation Unit: Student Services and Engagement; School of Science, Technology and Engineering
Language: English
Record Identifier: 99707484402621
Output Type: Journal article

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Collaboration types: Domestic collaboration
Web Of Science research areas: Chemistry, Organic

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