Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria
| Autor: | Katherine A. Hammer, Amy McKarral King, Paul A. Keller, Dena Lyras, Stephen Pyne, Steven M. Wales, Andrew J. Tague, Thomas V. Riley |
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| Rok vydání: | 2015 |
| Předmět: |
Peptidomimetic
Isostere Triazole Microbial Sensitivity Tests Gram-Positive Bacteria medicine.disease_cause Biochemistry Microbiology chemistry.chemical_compound Gram-Negative Bacteria medicine Humans Physical and Theoretical Chemistry Pathogen Clostridioides difficile Chemistry Organic Chemistry Pathogenic bacteria Dipeptides Triazoles Clostridium difficile Antimicrobial In vitro Anti-Bacterial Agents Peptidomimetics |
| Zdroj: | Organic & Biomolecular Chemistry. 13:5743-5756 |
| ISSN: | 1477-0539 1477-0520 |
| Popis: | 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)). |
| Databáze: | OpenAIRE |
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