Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteriaElectronic supplementary information (ESI) available: Experimental procedures, compound characterization data, antibacterial testing methods, hemolysis data and NMR spectra. See DOI: 10.1039/c5ob00576k

• Main Authors: Wales, Steven M, Hammer, Katherine A, King, Amy M, Tague, Andrew J, Lyras, Dena, Riley, Thomas V, Keller, Paul A, Pyne, Stephen G
• Format: Journal Article
• Language: English
• Published: 13.05.2015
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob00576k

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 ). Designed binaphthyl-based, cationic peptidomimetic antimicrobials targeting C. difficile , incorporating a click-derived 1,2,3-triazole ester isostere at the C-terminus MICs of 4 μg mL −1 against three human isolates of C. difficile .