Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model

Andrew J. Tague, Papanin Putsathit, Melanie L. Hutton, Katherine A. Hammer, Steven M. Wales, Daniel R. Knight, Thomas V. Riley, Dena Lyras, Paul A. Keller, Stephen G. Pyne

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3 Citations (Scopus)

Abstract

Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 mu g/mL against methicillin-resistant Staphylococcus aureus and 8 g/mL against C difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 mu g/mL), Pseudomonas aeruginosa (8 ugimL) and Klebsiella pneumoniae (16 ugimL); additionally, compound 50 displayed reduced haemolytic activity (

Original languageEnglish
Pages (from-to)203-224
Number of pages22
JournalEuropean Journal of Medicinal Chemistry
Volume170
DOIs
Publication statusPublished - 15 May 2019

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