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...
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| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0183457&type=printable |
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| author | 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 |
| author_facet | 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 |
| author_sort | Abiodun D Ogunniyi |
| collection | DOAJ |
| 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 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. |
| format | Article |
| id | doaj-art-aa814e3bdf3c4940b0c7e83142c96dc3 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-aa814e3bdf3c4940b0c7e83142c96dc32025-08-20T03:04:36ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01129e018345710.1371/journal.pone.0183457Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent.Abiodun D OgunniyiManouchehr KhazandiAndrew J StevensSarah K SimsStephen W PageSanjay GargHenrietta VenterAndrew PowellKaren WhiteKiro R PetrovskiGeraldine Laven-LawEliane G TótoliHérida R SalgadoHongfei PiGeoffrey W CoombsDean L ShinabargerJohn D TurnidgeJames C PatonAdam McCluskeyDarren J TrottThe 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0183457&type=printable |
| spellingShingle | 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 Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent. PLoS ONE |
| 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 | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0183457&type=printable |
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