Novel synthetic bis-indolic derivatives with antistaphylococcal activity, including against MRSA and VISA strains.
Objectives: We report the synthesis, antibacterial activity and toxicity of 24 bis-indolic derivatives obtained during the development of new ways of synthesis of marine bis-indole alkaloids from the spongotine, topsentin and hamacanthin classes.Methods: Innovative ways of synthesis and further stru...
| Publicado en: | Journal of Antimicrobial Chemotherapy (JAC) Vol. 70; no. 6; pp. 1727 - 1738 |
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| Autores principales: | , , , , , , , , , , , , |
| Formato: | Journal Article |
| Publicado: |
Oxford University Press / USA
Jun2015
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=109737671&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 109737671 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 03057453 N5O jtl: Journal of Antimicrobial Chemotherapy (JAC) issn: 03057453 maglogo: N pubinfo: dt: Jun2015 vid: 70 iid: 6 pid: 622 pub: Oxford University Press / USA artinfo: ui: 109737671 NLM25691323 2013019301 10.1093/jac/dkv015 NLM25691323 109737671 ppf: 1727 ppct: 11 formats: tig: atl: Novel synthetic bis-indolic derivatives with antistaphylococcal activity, including against MRSA and VISA strains. aug: au: Caspar, Yvan Jeanty, Matthieu Blu, Jérôme Burchak, Olga Le Pihive, Emmanuelle Maigre, Laure Schneider, Dominique Jolivalt, Claude Paris, Jean-Marc Hequet, Arnaud Minassian, Frédéric Denis, Jean-Noël Maurin, Max sug: ab: Objectives: We report the synthesis, antibacterial activity and toxicity of 24 bis-indolic derivatives obtained during the development of new ways of synthesis of marine bis-indole alkaloids from the spongotine, topsentin and hamacanthin classes.Methods: Innovative ways of synthesis and further structural optimizations led to bis-indoles presenting either the 1-(1H-indol-3'-yl)-1,2-diaminoethane unit or the 1-(1H-indol-3-yl)ethanamine unit. MIC determination was performed for reference and clinical strains of Staphylococcus aureus and CoNS species. MBC, time-kill kinetics, solubility, hydrophobicity index, plasma protein-binding and cytotoxicity assays were performed for lead compounds. Inhibition of the S. aureus NorA efflux pump was also tested for bis-indoles with no antistaphylococcal activity.Results: Lead compounds were active against both S. aureus and CoNS species, with MICs between 1 and 4 mg/L. Importantly, the same MICs were found for MRSA and vancomycin-intermediate S. aureus strains. Early concentration-dependent bactericidal activity was observed for lead derivatives. Compounds with no intrinsic antibacterial activity could inhibit the S. aureus NorA efflux pump, which is involved in resistance to fluoroquinolones. At 0.5 mg/L, the most effective compound led to an 8-fold reduction of the ciprofloxacin MIC for the SA-1199B S. aureus strain, which overexpresses NorA. However, the bis-indole compounds displayed a high hydrophobicity index and high plasma protein binding, which significantly reduced antibacterial activity.Conclusions: We have synthesized and characterized novel bis-indole derivatives as promising candidates for the development of new antistaphylococcal treatments, with preserved activity against MDR S. aureus strains. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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