Author Identifier

Thomas V. Riley

ORCID : 0000-0002-1351-3740

Document Type

Journal Article

Publication Title

Antibiotics

Volume

10

Issue

8

Publisher

MDPI

School

School of Medical and Health Sciences

RAS ID

38817

Funders

National Health and Medical Research Council

Grant Number

NHMRC Number : APP1145760

Grant Link

http://purl.org/au-research/grants/nhmrc/1145760

Comments

Mahadari, M. K., Jennepalli, S., Tague, A. J., Putsathit, P., Hutton, M. L., Hammer, K. A., . . . Pyne, S. G. (2021). 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, 10(8), article 913. https://doi.org/10.3390/antibiotics10080913

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.

DOI

10.3390/antibiotics10080913

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Research Themes

Health

Priority Areas

Safety and quality in health care

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