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.Leggett, J.E.2023-10-102023-10-102023Antimicrobial Agents and Chemotherapy, 2023; 67(10):e0042423-1-e0042423-130066-48041098-6596https://hdl.handle.net/2440/139651Published online: 11 September 2023We 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.en© 2023 American Society for Microbiology. All Rights Reserved.NCL195; colistin; Gram-positive bacteria; Gram-negative bacteria; multidrug resistance; bioluminescence; synergyJournal article10.1128/aac.00424-232023-07-07648824Woolford, L. [0000-0001-7271-2937]Ogunniyi, A. [0000-0001-9308-5629]Trott, D.J. [0000-0002-8297-5770]