Modelling antibiotic and cytotoxic isoquinoline effects inStaphylococcus aureus, Staphylococcus epidermidis and mammaliancells

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 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.