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

Journal Article


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Abstract


  • lostridium 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 μg 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 μg mL−1), S. pneumoniae (MICs ≥1 μg mL−1), E. coli (MICs ≥4 μg mL−1), A. baumannii (MICs ≥4 μg mL−1) and vancomycin-resistant E. faecalis (MICs ≥4 μg mL−1).

Authors


  •   Wales, Steven M. (external author)
  •   Hammer, Katherine A. (external author)
  •   King, Amy M. (external author)
  •   Tague, Andrew (external author)
  •   Lyras, Dena (external author)
  •   Riley, Thomas V. (external author)
  •   Keller, Paul A.
  •   Pyne, Stephen G.

Publication Date


  • 2015

Citation


  • Wales, S. M., Hammer, K. A., King, A. M., Tague, A., Lyras, D., Riley, T. V., Keller, P. A. & Pyne, S. G. (2015). Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria. Organic and Biomolecular Chemistry, 13 (20), 5743-5756.

Scopus Eid


  • 2-s2.0-84929378608

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=3875&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/2853

Number Of Pages


  • 13

Start Page


  • 5743

End Page


  • 5756

Volume


  • 13

Issue


  • 20

Abstract


  • lostridium 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 μg 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 μg mL−1), S. pneumoniae (MICs ≥1 μg mL−1), E. coli (MICs ≥4 μg mL−1), A. baumannii (MICs ≥4 μg mL−1) and vancomycin-resistant E. faecalis (MICs ≥4 μg mL−1).

Authors


  •   Wales, Steven M. (external author)
  •   Hammer, Katherine A. (external author)
  •   King, Amy M. (external author)
  •   Tague, Andrew (external author)
  •   Lyras, Dena (external author)
  •   Riley, Thomas V. (external author)
  •   Keller, Paul A.
  •   Pyne, Stephen G.

Publication Date


  • 2015

Citation


  • Wales, S. M., Hammer, K. A., King, A. M., Tague, A., Lyras, D., Riley, T. V., Keller, P. A. & Pyne, S. G. (2015). Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria. Organic and Biomolecular Chemistry, 13 (20), 5743-5756.

Scopus Eid


  • 2-s2.0-84929378608

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=3875&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/2853

Number Of Pages


  • 13

Start Page


  • 5743

End Page


  • 5756

Volume


  • 13

Issue


  • 20