title: Modelling antibiotic and cytotoxic isoquinoline effects in Staphylococcus aureus, Staphylococcus epidermidis and mammalian cells.
abstract: Isoquinolines (IQs) are natural substances with an antibiotic potential we aim to optimize. Specifically, IQ-238 is a synthetic analog of the novel-type N,C-coupled naphthylisoquinoline (NIQ) alkaloid ancisheynine. Recently, we developed and tested other IQs such as IQ-143. By utilizing genome-wide gene expression data, metabolic network modelling and Voronoi tessalation based data analysis - as well as cytotoxicity measurements, chemical properties calculations and principal component analysis of the NIQs - we show that IQ-238 has strong antibiotic potential for staphylococci and low cytotoxicity against murine or human cells. Compared to IQ-143, systemic effects are less pronounced. Most enzyme activity changes due to IQ-238 are located in the carbohydrate metabolism. Validation includes metabolite measurements on biological replicates. IQ-238 delineates key properties and a chemical space for a good therapeutic window. The combination of analysis methods allows suggestions for further lead development and yields an in-depth look at staphylococcal adaptation and network changes after antibiosis. Results are compared to eukaryotic host cells.
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Cecil
authors.affiliation: University of Würzburg, Institute for Molecular-Infection Biology, 97070 Würzburg, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Ohlsen
authors.affiliation: University of Würzburg, Institute for Molecular-Infection Biology, 97070 Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Menzel
authors.affiliation: Genomic Research Laboratory, Service of Infectious Diseases, University of Geneva Hospitals, Rue Gabrielle-Perret-Gentil 4, CH-1211 Geneva 14, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: François
authors.affiliation: Genomic Research Laboratory, Service of Infectious Diseases, University of Geneva Hospitals, Rue Gabrielle-Perret-Gentil 4, CH-1211 Geneva 14, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Schrenzel
authors.affiliation: Genomic Research Laboratory, Service of Infectious Diseases, University of Geneva Hospitals, Rue Gabrielle-Perret-Gentil 4, CH-1211 Geneva 14, Switzerland.
authors.forename: Adrien
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Institute of Biochemistry, Ernst-Moritz-Arndt-University Greifswald, Felix-Hausdorff-Straße 4, D-17487 Greifswald, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Dörries
authors.affiliation: University of Würzburg, Institute for Molecular-Infection Biology, 97070 Würzburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Selle
authors.affiliation: Institute of Biochemistry, Ernst-Moritz-Arndt-University Greifswald, Felix-Hausdorff-Straße 4, D-17487 Greifswald, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lalk
authors.affiliation: University of Würzburg, Institute for Molecular-Infection Biology, 97070 Würzburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hantzschmann
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Liang
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt-University Greifswald, Friedrich-Ludwig-Jahn Strasse 15, D-17487 Greifswald, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bernhardt
authors.affiliation: University of Würzburg, Institute for Molecular-Infection Biology, 97070 Würzburg, Germany.
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Ölschläger
authors.affiliation: University of Würzburg, Institute for Organic Chemistry, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.affiliation: University of Würzburg, Institute for Molecular-Infection Biology, 97070 Würzburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Bruhn
authors.affiliation: University of Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Unger
authors.affiliation: Laboratory of Molecular Physiology, Universidad Central de Venezuela, Caracas, Venezuela.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
authors.affiliation: University of Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Leane
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany; EMBL Heidelberg, BioComputing Unit, Meyerhofstraße 1, 69117 Heidelberg, Germany. Electronic address: dandekar@biozentrum.uni-wuerzburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity*; D002460:Cell Line; D019295:Computational Biology; D020869:Gene Expression Profiling; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology* / Q000633:toxicity*; D053858:Metabolic Networks and Pathways; D051379:Mice; D013211:Staphylococcus aureus / Q000187:drug effects*; D013212:Staphylococcus epidermidis / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D007546:Isoquinolines; C039109:isoquinoline
keywords: Extreme pathway analysis; Gene expression; Infection; Metabolism; Metabolites; Principal component analysis; Voronoi tessalation