Oral administration of a 2-aminopyrimidine robenidine analogue (NCL195) significantly reduces infection and reduces infection in combination with sub-inhibitory colistin concentrations in a bioluminescent mouse model.
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
Author Information
Hang Thi Nguyen: Australian Center for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide , Adelaide, South Australia, Australia.
Henrietta Venter: Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia , Adelaide, South Australia, Australia.
Lucy Woolford: School of Animal and Veterinary Sciences, The University of Adelaide , Adelaide, South Australia, Australia.
Kelly A Young: Chemistry, School of Environmental and Life Sciences, University of Newcastle , Callaghan, New South Wales, Australia.
Adam McCluskey: Chemistry, School of Environmental and Life Sciences, University of Newcastle , Callaghan, New South Wales, Australia.
Sanjay Garg: Clinical and Health Sciences, University of South Australia , Adelaide, South Australia, Australia.
Sylvia S Sapula: Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia , Adelaide, South Australia, Australia.
Stephen W Page: Neoculi Pty Ltd. , Burwood, Victoria, Australia.
Abiodun David Ogunniyi: Australian Center for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide , Adelaide, South Australia, Australia.
Darren J Trott: Australian Center for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide , Adelaide, South Australia, Australia. ORCID
We have previously reported promising 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 and peritonitis-sepsis models. Four oral doses of 50 mg/kg NCL195, commencing immediately post-infection, were administered at 4 h intervals in the 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 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 infection. In the infection model, oral treatment of mice with NCL195 resulted in significantly reduced infection loads ( < 0.01) and longer survival times ( < 0.001) than vehicle-only treated mice. In the infection model, co-administration of NCL195 and graded doses of colistin resulted in a dose-dependent significant reduction in colistin-susceptible ( < 0.01) or colistin-resistant ( < 0.05) 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.
