- 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
- Creator
- Nguyen, Hang Thi; Venter, Henrietta; Woolford, Lucy; Young, Kelly A.; Mccluskey, Adam; Garg, Sanjay; Sapula, Sylvia S.; Page, Stephen W.; Ogunniyi, Abiodun David; Trott, Darren J.
- Relation
- ARC.LP110200770 http://purl.org/au-research/grants/arc/LP110200770
- Relation
- Antimicrobial Agents and Chemotherapy Vol. 67, Issue 10, no. e00424-23
- Publisher Link
- http://dx.doi.org/10.1128/aac.00424-23
- Publisher
- American Society for Microbiology
- Resource Type
- journal article
- Date
- 2023
- Description
- 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.
- Subject
- NCL195; colistin; Gram-positive bacteria; Gram-negative bacteria; multidrug resistance; bioluminescence
- Identifier
- http://hdl.handle.net/1959.13/1494093
- Identifier
- uon:53705
- Identifier
- ISSN:0066-4804
- Language
- eng
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