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

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

  • Eur J Med Chem. 2019 May 15:170:203-224. doi: 10.1016/j.ejmech.2019.02.068.
Andrew J Tague 1,  Papanin Putsathit 2,  Melanie L Hutton 3,  Katherine A Hammer 4,  Steven M Wales 5,  Daniel R Knight 6,  Thomas V Riley 7,  Dena Lyras 3,  Paul A Keller 8,  Stephen G Pyne 9
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Electronic address: atague@uow.edu.au.
  • 2 School of Medical and Health Sciences, Edith Cowan University, Western Australia, 6027, Australia.
  • 3 Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, 3800, Australia.
  • 4 School of Biomedical Sciences, The University of Western Australia, Western Australia, 6009, Australia.
  • 5 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia.
  • 6 School of Veterinary and Life Sciences, Murdoch University, Western Australia, 6150, Australia.
  • 7 School of Medical and Health Sciences, Edith Cowan University, Western Australia, 6027, Australia; School of Biomedical Sciences, The University of Western Australia, Western Australia, 6009, Australia; School of Veterinary and Life Sciences, Murdoch University, Western Australia, 6150, Australia; PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Western Australia, 6009, Australia.
  • 8 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Electronic address: keller@uow.edu.au.
  • 9 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia. Electronic address: spyne@uow.edu.au.
PMID: 30901686 DOI: 10.1016/j.ejmech.2019.02.068
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 μg/mL against methicillin-resistant Staphylococcus aureus and 8 μg/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 μg/mL), Pseudomonas aeruginosa (8 μg/mL) and Klebsiella pneumoniae (16 μg/mL); additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized amphiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile Infection by reducing the severity and slowing the onset of disease.

Keywords

Antibacterial; Biaryl cationic amphiphiles; Clostridioides (Clostridium) difficile; Peptidomimetic; Triazole.

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