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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

18 Citations (Scopus)

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 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).

Original languageEnglish
Pages (from-to)5743-5756
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number20
DOIs
Publication statusPublished - 28 May 2015

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