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Title

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

Authors
Cecil, Alexander
Ohlsen, Knut
Menzel, Thomas
Dörries, Kirsten
Selle, Martina
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Published in International Journal of Medical Microbiology. 2015, vol. 305, no. 1, p. 96-109
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.
Identifiers
PMID: 25500547
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Research group Analyse génomique et fonctionnelle du staphylocoque doré (604)
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CECIL, Alexander et al. Modelling antibiotic and cytotoxic isoquinoline effects in Staphylococcus aureus, Staphylococcus epidermidis and mammalian cells. In: International Journal of Medical Microbiology, 2015, vol. 305, n° 1, p. 96-109. https://archive-ouverte.unige.ch/unige:74151

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Deposited on : 2015-07-15

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