Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent

Abiodun D Ogunniyi; Manouchehr Khazandi; Andrew J Stevens; Sarah K Sims; Stephen W Page; Sanjay Garg; Henrietta Venter; Andrew Powell; Karen White; Kiro R Petrovski; Geraldine Laven-Law; Eliane G Tótoli; Hérida R Salgado; Hongfei Pi; Geoffrey W Coombs; Dean L Shinabarger; John D Turnidge; James C Paton; Adam McCluskey; Darren J Trott

doi:10.1371/journal.pone.0183457

Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent

PLoS One. 2017 Sep 5;12(9):e0183457. doi: 10.1371/journal.pone.0183457. eCollection 2017.

Authors

Abiodun D Ogunniyi¹, Manouchehr Khazandi¹, Andrew J Stevens², Sarah K Sims³, Stephen W Page⁴, Sanjay Garg⁵, Henrietta Venter⁶, Andrew Powell⁷, Karen White⁷, Kiro R Petrovski¹, Geraldine Laven-Law³, Eliane G Tótoli⁸, Hérida R Salgado⁸, Hongfei Pi¹, Geoffrey W Coombs^{9

10}, Dean L Shinabarger¹¹, John D Turnidge^{1

12}, James C Paton¹³, Adam McCluskey², Darren J Trott¹

Affiliations

¹ Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, South Australia, Australia.
² Chemistry, School of Environmental & Life Sciences, The University of Newcastle, Callaghan, New South Wales, Australia.
³ School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, South Australia, Australia.
⁴ Neoculi Pty Ltd, Burwood, Victoria, Australia.
⁵ Centre for Pharmaceutical Innovation and Development, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
⁶ School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
⁷ Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
⁸ Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, São Paulo, Brazil.
⁹ Department of Microbiology, Path West Laboratory Medicine-WA, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.
¹⁰ School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia, Australia.
¹¹ Micromyx LLC, Kalamazoo, Michighan, United States of America.
¹² Department of Molecular and Cellular Biology, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
¹³ Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

Abstract

The spread of multidrug resistance among bacterial pathogens poses a serious threat to public health worldwide. Recent approaches towards combating antimicrobial resistance include repurposing old compounds with known safety and development pathways as new antibacterial classes with novel mechanisms of action. Here we show that an analog of the anticoccidial drug robenidine (4,6-bis(2-((E)-4-methylbenzylidene)hydrazinyl)pyrimidin-2-amine; NCL195) displays potent bactericidal activity against Streptococcus pneumoniae and Staphylococcus aureus by disrupting the cell membrane potential. NCL195 was less cytotoxic to mammalian cell lines than the parent compound, showed low metabolic degradation rates by human and mouse liver microsomes, and exhibited high plasma concentration and low plasma clearance rates in mice. NCL195 was bactericidal against Acinetobacter spp and Neisseria meningitidis and also demonstrated potent activity against A. baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. in the presence of sub-inhibitory concentrations of ethylenediaminetetraacetic acid (EDTA) and polymyxin B. These findings demonstrate that NCL195 represents a new chemical lead for further medicinal chemistry and pharmaceutical development to enhance potency, solubility and selectivity against serious bacterial pathogens.

MeSH terms

Animals
Anti-Bacterial Agents / blood
Anti-Bacterial Agents / pharmacology*
Cell Line
Cell Membrane / drug effects
Cell Membrane / metabolism
Drug Resistance, Bacterial / drug effects
Enterococcus / drug effects
Hemolysis / drug effects
Humans
Mice
Microbial Sensitivity Tests
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Robenidine / analogs & derivatives*
Robenidine / pharmacology*
Staphylococcus aureus / drug effects
Streptococcus pneumoniae / drug effects
Structure-Activity Relationship
Time Factors
Vancomycin / pharmacology

Substances

Anti-Bacterial Agents
Robenidine
Vancomycin

Grants and funding

This work was supported by an Australian Research Council (ARC; arc.gov.au) Linkage grant (LP110200770) to D.J.T., A.M. and S.W.P. with Neoculi Pty Ltd as the Partner Organization. Additionally, it was funded in part by a grant from the National Health and Medical Research Council of Australia (NHMRC; nhmrc.gov.au) Program Grant 565526 to J.C.P., Project Grant 627142 to J.C.P. and A.D.O., and University of South Australia and the Sansom Institute of Health Research fund to H.V. Micromyx LLC provided support in the form of salary for D.L.S., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of all authors are articulated in the ‘author contributions’ section.