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

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dc.contributor.authorNguyen, H.T.
dc.contributor.authorVenter, H.
dc.contributor.authorWoolford, L.
dc.contributor.authorYoung, K.A.
dc.contributor.authorMcCluskey, A.
dc.contributor.authorGarg, S.
dc.contributor.authorSapula, S.S.
dc.contributor.authorPage, S.W.
dc.contributor.authorOgunniyi, A.
dc.contributor.authorTrott, D.J.
dc.contributor.editorLeggett, J.E.
dc.date.issued2023
dc.descriptionPublished online: 11 September 2023
dc.description.abstractWe 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.
dc.description.statementofresponsibilityHang 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
dc.identifier.citationAntimicrobial Agents and Chemotherapy, 2023; 67(10):e0042423-1-e0042423-13
dc.identifier.doi10.1128/aac.00424-23
dc.identifier.issn0066-4804
dc.identifier.issn1098-6596
dc.identifier.orcidWoolford, L. [0000-0001-7271-2937]
dc.identifier.orcidOgunniyi, A. [0000-0001-9308-5629]
dc.identifier.orcidTrott, D.J. [0000-0002-8297-5770]
dc.identifier.urihttps://hdl.handle.net/2440/139651
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.relation.granthttp://purl.org/au-research/grants/arc/LP110200770
dc.rights© 2023 American Society for Microbiology. All Rights Reserved.
dc.source.urihttps://doi.org/10.1128/aac.00424-23
dc.subjectNCL195; colistin; Gram-positive bacteria; Gram-negative bacteria; multidrug resistance; bioluminescence; synergy
dc.titleOral 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
dc.typeJournal article
pubs.publication-statusPublished

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