Modelling antibiotic and cytotoxic isoquinoline effects in Staphylococcus aureus, Staphylococcus epidermidis and mammalian cells.
Int J Med Microbiol, 2015/1;305(1):96-109.
Cecil A[1], Ohlsen K[2], Menzel T[2], François P[3], Schrenzel J[3], Fischer A[3], Dörries K[4], Selle M[2], Lalk M[4], Hantzschmann J[2], Dittrich M[1], Liang C[1], Bernhardt J[5], Ölschläger TA[2], Bringmann G[6], Bruhn H[2], Unger M[7], Ponte-Sucre A[8], Lehmann L[7], Dandekar T[9]
Affiliations
PMID: 25500547
Impact factor: 3.658
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.
Keywords: Extreme pathway analysis; Gene expression; Infection; Metabolism; Metabolites; Principal component analysis; Voronoi tessalation
MeSH terms
Animals; Anti-Bacterial Agents; Cell Line; Computational Biology; Gene Expression Profiling; Humans; Isoquinolines; Metabolic Networks and Pathways; Mice; Staphylococcus aureus; Staphylococcus epidermidis
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