Journal article
Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model
European Journal of Medicinal Chemistry, Vol.170, pp.203-224
2019
PMID: 30901686
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 (<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.
Details
- Title
- Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model
- Authors
- Andrew J. Tague (Corresponding Author) - University of WollongongPapanin Putsathit (Author) - Edith Cowan UniversityMelanie L. Hutton (Author) - Monash UniversityKatherine A. Hammer (Author) - University of Western AustraliaSteven M. Wales (Author) - University of WollongongDaniel R. Knight (Author) - Murdoch UniversityThomas V. Riley (Author) - University of Western AustraliaDena Lyras (Author) - Monash UniversityPaul A. Keller (Corresponding Author) - University of WollongongStephen G. Pyne (Corresponding Author) - University of Wollongong
- Publication details
- European Journal of Medicinal Chemistry, Vol.170, pp.203-224
- Publisher
- Elsevier Masson
- DOI
- 10.1016/j.ejmech.2019.02.068
- ISSN
- 1768-3254
- PMID
- 30901686
- Grant note
- APP1124032 / Australian National Health and Medical Research Council (NHMRC)
- Organisation Unit
- Student Services and Engagement; School of Science, Technology and Engineering
- Language
- English
- Record Identifier
- 99707363902621
- Output Type
- Journal article
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- Domestic collaboration
- Web Of Science research areas
- Chemistry, Medicinal
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Source: InCites