Modelling antibiotic and cytotoxic isoquinoline effects in Staphylococcus aureus, Staphylococcus epidermidis and mammalian cells.

International journal of medical microbiology : IJMM 2015 Jan

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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. Copyright © 2014 Elsevier GmbH. All rights reserved.

Citation

Alexander Cecil, Knut Ohlsen, Thomas Menzel, Patrice François, Jacques Schrenzel, Adrien Fischer, Kirsten Dörries, Martina Selle, Michael Lalk, Julia Hantzschmann, Marcus Dittrich, Chunguang Liang, Jörg Bernhardt, Tobias A Ölschläger, Gerhard Bringmann, Heike Bruhn, Matthias Unger, Alicia Ponte-Sucre, Leane Lehmann, Thomas Dandekar. Modelling antibiotic and cytotoxic isoquinoline effects in Staphylococcus aureus, Staphylococcus epidermidis and mammalian cells. International journal of medical microbiology : IJMM. 2015 Jan;305(1):96-109