Journal article
Cationic peptidomimetic amphiphiles having a N-aryl- or N-naphthyl-1,2,3-triazole core structure targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation, and an in vivo C. difficile infection model
Antibiotics, Vol.10(8), Article 913
2021
Abstract
Clostridioides (also known as Clostridium) difficile is a Gram-positive anaerobic, spore producing bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are inadequate, expensive, and limited, and thus inexpensive drug treatments for C. difficile infection (CDI) with improved efficacy and specificity are urgently needed. To improve the solubility of our cationic amphiphilic 1,1′-binaphthylpeptidomimetics developed earlier that showed promise in an in vivo murine CDI model we have synthesized related compounds with an N-arytriazole or N-naphthyltriazole moiety instead of the 1,1′-biphenyl or 1,1′-binaphthyl moiety. This modification was made to increase the polarity and thus water solubility of the overall peptidomimetics, while maintaining the aromatic character. The dicationic N-naphthyltriazole derivative 40 was identified as a C. difficile-selective antibacterial with MIC values of 8 µg/mL against C. difficile strains ATCC 700057 and 132 (both ribotype 027). This compound displayed increased water solubility and reduced hemolytic activity (32 µg/mL) in an in vitro hemolysis assay and reduced cytotoxicity (CC50 32 µg/mL against HEK293 cells) relative to lead compound 2. Compound 40 exhibited mild efficacy (with 80% survival observed after 24 h compared to the DMSO control of 40%) in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.
Details
- Title
- Cationic peptidomimetic amphiphiles having a N-aryl- or N-naphthyl-1,2,3-triazole core structure targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation, and an in vivo C. difficile infection model
- Authors/Creators
- M.K. Mahadari (Author/Creator) - University of WollongongS. Jennepalli (Author/Creator) - University of WollongongA.J. Tague (Author/Creator) - University of WollongongP. Putsathit (Author/Creator) - Edith Cowan UniversityM.L. Hutton (Author/Creator) - Monash UniversityK.A. Hammer (Author/Creator) - The University of Western AustraliaD.R. Knight (Author/Creator) - The University of Western AustraliaT.V. Riley (Author/Creator) - Edith Cowan UniversityD. Lyras (Author/Creator) - Monash UniversityP.A. Keller (Author/Creator) - University of WollongongS.G. Pyne (Author/Creator) - University of Wollongong
- Publication Details
- Antibiotics, Vol.10(8), Article 913
- Publisher
- MDPI
- Identifiers
- 991005541616207891
- Copyright
- © 2021 by the authors
- Murdoch Affiliation
- Centre for Biosecurity and One Health; Harry Butler Institute
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
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- Citation topics
- 1 Clinical & Life Sciences
- 1.120 Inflammatory Bowel Diseases & Infections
- 1.120.1133 Clostridium Infections
- Web Of Science research areas
- Infectious Diseases
- Pharmacology & Pharmacy
- ESI research areas
- Pharmacology & Toxicology