Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
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Public Library of Science
2017
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| Online Access: | http://hdl.handle.net/20.500.11937/70126 |
| _version_ | 1848762222110572544 |
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| 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, Geoffrey Shinabarger, D. Turnidge, J. Paton, J. McCluskey, A. Trott, D. |
| author_facet | 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, Geoffrey Shinabarger, D. Turnidge, J. Paton, J. McCluskey, A. Trott, D. |
| author_sort | Ogunniyi, A. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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 ethylenediaminetetra-acetic 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. |
| first_indexed | 2025-11-14T10:44:08Z |
| format | Journal Article |
| id | curtin-20.500.11937-70126 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:44:08Z |
| publishDate | 2017 |
| publisher | Public Library of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-701262018-08-23T00:53:17Z Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent 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, Geoffrey Shinabarger, D. Turnidge, J. Paton, J. McCluskey, A. Trott, D. 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 ethylenediaminetetra-acetic 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. 2017 Journal Article http://hdl.handle.net/20.500.11937/70126 10.1371/journal.pone.0183457 http://creativecommons.org/licenses/by/4.0/ Public Library of Science fulltext |
| spellingShingle | 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, Geoffrey Shinabarger, D. Turnidge, J. Paton, J. McCluskey, A. Trott, D. Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent |
| title | Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent |
| title_full | Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent |
| title_fullStr | Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent |
| title_full_unstemmed | Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent |
| title_short | Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent |
| title_sort | evaluation of robenidine analog ncl195 as a novel broad-spectrum antibacterial agent |
| url | http://hdl.handle.net/20.500.11937/70126 |