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

被引：14

作者：

Cecil, Alexander ^{[1
]}

Ohlsen, Knut ^{[2
]}

Menzel, Thomas ^{[2
]}

Francois, Patrice ^{[3
]}

Schrenzel, Jacques ^{[3
]}

Fischer, Adrien ^{[3
]}

Doerries, Kirsten ^{[4
]}

Selle, Martina ^{[2
]}

Lalk, Michael ^{[4
]}

Hantzschmann, Julia ^{[2
]}

Dittrich, Marcus ^{[1
]}

Liang, Chunguang ^{[1
]}

Bernhardt, Joerg ^{[5
]}

Oelschlaeger, Tobias A. ^{[2
]}

Bringmann, Gerhard ^{[6
]}

Bruhn, Heike ^{[2
]}

Unger, Matthias ^{[7
]}

Ponte-Sucre, Alicia ^{[8
]}

Lehmann, Leane ^{[7
]}

Dandekar, Thomas ^{[1
,9
]}

机构：

[1] Univ Wurzburg, Dept Bioinformat, Bioctr, D-97074 Wurzburg, Germany

[2] Univ Wurzburg, Inst Mol Infect Biol, D-97074 Wurzburg, Germany

[3] Univ Hosp Geneva, Infect Dis Serv, Genom Res Lab, CH-1211 Geneva 14, Switzerland

[4] Univ Greifswald, Inst Biochem, D-17487 Greifswald, Germany

[5] Univ Greifswald, Inst Microbiol, D-17487 Greifswald, Germany

[6] Univ Wurzburg, Inst Organ Chem, D-97074 Wurzburg, Germany

[7] Univ Wurzburg, Inst Pharm & Food Chem, D-97074 Wurzburg, Germany

[8] Cent Univ Venezuela, Lab Mol Physiol, Caracas, Venezuela

[9] EMBL Heidelberg, BioComp Unit, D-69117 Heidelberg, Germany

来源：

INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY | 2015年 / 305卷 / 01期

关键词：

Metabolism; Infection; Extreme pathway analysis; Gene expression; Voronoi tessalation; Principal component analysis; Metabolites; GENE-EXPRESSION; NAPHTHYLISOQUINOLINE ALKALOIDS; GENOME; VIRULENCE; MBGD; ANCISTROCLADINIUM; ANCISHEYNINE; PREDICTIONS; RESISTANCE; EVOLUTION;

D O I：

10.1016/j.ijmm.2014.11.006

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Isoquinolines (IQs) are natural substances with an antibiotic potential we aim to optimize. Specifically, IQ-238 is a synthetic analog of the novel-type NC-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. (C) 2014 Elsevier GmbH. All rights reserved.

引用

页码：96 / 109

页数：14

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