Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/139651
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Type: | Journal article |
Title: | Oral administration of a 2-aminopyrimidine robenidine analogue (NCL195) significantly reduces Staphylococcus aureus infection and reduces Escherichia coli infection in combination with sub-inhibitory colistin concentrations in a bioluminescent mouse model |
Author: | Nguyen, H.T. Venter, H. Woolford, L. Young, K.A. McCluskey, A. Garg, S. Sapula, S.S. Page, S.W. Ogunniyi, A. Trott, D.J. |
Citation: | Antimicrobial Agents and Chemotherapy, 2023; 67(10):e0042423-1-e0042423-13 |
Publisher: | American Society for Microbiology |
Issue Date: | 2023 |
ISSN: | 0066-4804 1098-6596 |
Editor: | Leggett, J.E. |
Statement of Responsibility: | Hang Thi Nguyen, Henrietta Venter, Lucy Woolford, Kelly A. Young, Adam McCluskey, Sanjay Garg, Sylvia S. Sapula, Stephen W. Page, Abiodun David Ogunniyi, Darren J. Trott |
Abstract: | We have previously reported promising in vivo activity of the first-generation 2-aminopyramidine robenidine analogue NCL195 against Gram-positive bacteria (GPB) when administered via the systemic route. In this study, we examined the efficacy of oral treatment with NCL195 (± low-dose colistin) in comparison to oral moxifloxacin in bioluminescent Staphylococcus aureus and Escherichia coli peritonitis-sepsis models. Four oral doses of 50 mg/kg NCL195, commencing immediately post-infection, were administered at 4 h intervals in the S. aureus peritonitis-sepsis model. We used a combination of four oral doses of 50 mg/kg NCL195 and four intraperitoneal doses of colistin at 0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg in the E. coli peritonitis-sepsis model. Subsequently, the dose rates of four intraperitoneal doses of colistin were increased to 0.5 mg/kg, 1 mg/kg, or 2 mg/kg at 4 h intervals to treat a colistin-resistant E. coli infection. In the S. aureus infection model, oral treatment of mice with NCL195 resulted in significantly reduced S. aureus infection loads (P < 0.01) and longer survival times (P < 0.001) than vehicle-only treated mice. In the E. coli infection model, co-administration of NCL195 and graded doses of colistin resulted in a dose-dependent significant reduction in colistin-susceptible (P < 0.01) or colistin-resistant (P < 0.05) E. coli loads compared to treatment with colistin alone at similar concentrations. Our results confirm that NCL195 is a potential candidate for further preclinical development as a specific treatment for multidrug-resistant infections, either as a stand-alone antibiotic for GPB or in combination with sub-inhibitory concentrations of colistin for Gram-negative bacteria. |
Keywords: | NCL195; colistin; Gram-positive bacteria; Gram-negative bacteria; multidrug resistance; bioluminescence; synergy |
Description: | Published online: 11 September 2023 |
Rights: | © 2023 American Society for Microbiology. All Rights Reserved. |
DOI: | 10.1128/aac.00424-23 |
Grant ID: | http://purl.org/au-research/grants/arc/LP110200770 |
Published version: | http://dx.doi.org/10.1128/aac.00424-23 |
Appears in Collections: | Animal and Veterinary Sciences publications |
Files in This Item:
File | Description | Size | Format | |
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hdl_139651.pdf | Accepted version | 5.02 MB | Adobe PDF | View/Open |
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