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Type: Journal article
Title: Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent
Author: Ogunniyi, A.
Khazandi, M.
Stevens, A.
Sims, S.
Page, S.
Garg, S.
Venter, H.
Powell, A.
White, K.
Petrovski, K.
Laven-Law, G.
Tótoli, E.
Salgado, H.
Pi, H.
Coombs, G.
Shinabarger, D.
Turnidge, J.
Paton, J.
McCluskey, A.
Trott, D.
Citation: PLoS One, 2017; 12(9):e0183457-1-e0183457-23
Publisher: Public Library Science
Issue Date: 2017
ISSN: 1932-6203
Editor: Virolle, M.-J.
Statement of
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
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.
Keywords: Staphylococcus aureus
Rights: © 2017 Ogunniyi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI: 10.1371/journal.pone.0183457
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