title: Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells.
abstract: BACKGROUND
  Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine.
  
  
  RESULTS
  Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity.
  
  
  CONCLUSIONS
  The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics.
authors.affiliation: University of Würzburg, Theodor-Boveri Institute, Department of Bioinformatics, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Cecil
authors.forename: Carina
authors.initials: C
authors.lastname: Rikanović
authors.forename: Knut
authors.initials: K
authors.lastname: Ohlsen
authors.forename: Chunguang
authors.initials: C
authors.lastname: Liang
authors.forename: Jörg
authors.initials: J
authors.lastname: Bernhardt
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Oelschlaeger
authors.forename: Tanja
authors.initials: T
authors.lastname: Gulder
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Matthias
authors.initials: M
authors.lastname: Unger
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D053858:Metabolic Networks and Pathways; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D013212:Staphylococcus epidermidis / Q000187:drug effects* / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D000900:Anti-Bacterial Agents; C569371:IQ-143 compound; D007546:Isoquinolines; D009281:Naphthalenes