title: Novel synthetic bis-indolic derivatives with antistaphylococcal activity, including against MRSA and VISA strains.
abstract: OBJECTIVE
  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.
authors.affiliation: Laboratoire de bactériologie, Centre Hospitalier Universitaire de Grenoble, CS10217, 38043 Grenoble cedex 9, France Université Grenoble Alpes, CNRS, LAPM, F-38000 Grenoble, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Caspar
authors.affiliation: Université Grenoble Alpes, CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Jeanty
authors.affiliation: Université Grenoble Alpes, CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Blu
authors.affiliation: Université Grenoble Alpes, CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Burchak
authors.affiliation: Université Grenoble Alpes, CNRS, LAPM, F-38000 Grenoble, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Le Pihive
authors.affiliation: Université Grenoble Alpes, CNRS, LAPM, F-38000 Grenoble, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Maigre
authors.affiliation: Université Grenoble Alpes, CNRS, LAPM, F-38000 Grenoble, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schneider
authors.affiliation: Chimie ParisTech, Laboratoire Charles Friedel, 75005 Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Jolivalt
authors.affiliation: Chimie ParisTech, Laboratoire Charles Friedel, 75005 Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Paris
authors.affiliation: Chimie ParisTech, Laboratoire Charles Friedel, 75005 Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Hequet
authors.affiliation: Université Grenoble Alpes, CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Minassian
authors.affiliation: Université Grenoble Alpes, CNRS, DCM, F-38000 Grenoble, France.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Denis
authors.affiliation: Laboratoire de bactériologie, Centre Hospitalier Universitaire de Grenoble, CS10217, 38043 Grenoble cedex 9, France Université Grenoble Alpes, CNRS, LAPM, F-38000 Grenoble, France mmaurin@chu-grenoble.fr.
authors.forename: Max
authors.initials: M
authors.lastname: Maurin
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D048288:Imidazolines / Q000737:chemistry; D026121:Indole Alkaloids / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D011719:Pyrazines / Q000737:chemistry; D013210:Staphylococcus / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000470:Alkaloids; D000900:Anti-Bacterial Agents; D007093:Imidazoles; D048288:Imidazolines; D026121:Indole Alkaloids; D007211:Indoles; D011719:Pyrazines; C525418:spongotine A; C070184:topsentin; C091307:hamacanthine A
keywords: antibiotics; bis-indoles; drug development; drug susceptibility testing; efflux pumps; staphylococci