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Título : Modelling antibiotic and cytotoxic isoquinoline effects inStaphylococcus aureus, Staphylococcus epidermidis and mammaliancells
Autor : Cecil, Alexander
Ohlsen, Knut
Menzel, Thomas
Francois, Patrice
Schrenzel, Jacques
Fischer, Adrien
Dörries, Kirsten
Selle, Martina
Lalk, Michael
Hantzschmann, Julia
Dittrich, Marcus
Liang, Chunguang
Bernhardt, Jörg
Ölschläger, Tobias
Bringmann, Gerhard
Bruhn, Heike
Unger, Matthias
Ponte-Sucre, Alicia
Lehmann, Leane
Dandekar, Thomas
Palabras clave : metabolism
pathway analysis
gene expression
Fecha de publicación : 5-Mar-2015
Citación : International Journal of Medical Microbiology;305:96-109, 2015
Resumen : 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 expressiondata, metabolic network modelling and Voronoi tessalation based data analysis – as well as cytotoxicitymeasurements, chemical properties calculations and principal component analysis of the NIQs – weshow that IQ-238 has strong antibiotic potential for staphylococci and low cytotoxicity against murine orhuman cells. Compared to IQ-143, systemic effects are less pronounced. Most enzyme activity changesdue to IQ-238 are located in the carbohydrate metabolism. Validation includes metabolite measurementson biological replicates. IQ-238 delineates key properties and a chemical space for a good therapeuticwindow. The combination of analysis methods allows suggestions for further lead development andyields an in-depth look at staphylococcal adaptation and network changes after antibiosis. Results arecompared to eukaryotic host cells.
ISSN : 1438-4221
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