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

共 45 条

[11] Genetic requirements for Staphylococcus aureus abscess formation and persistence in host tissues [J].

Cheng, Alice G. ;

Kim, Hwan Keun ;

Burts, Monica L. ;

Krausz, Thomas ;

Schneewind, Olaf ;

Missiakas, Dominique M. .

FASEB JOURNAL, 2009, 23 (10) :3393-3404

[12] Using ANOVA to analyze microarray data [J].

Churchill, GA .

BIOTECHNIQUES, 2004, 37 (02) :173-+

[13] Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus [J].

Diep, BA ;

Gill, SR ;

Chang, RF ;

Phan, TH ;

Chen, JH ;

Davidson, MG ;

Lin, F ;

Lin, J ;

Carleton, HA ;

Mongodin, EF ;

Sensabaugh, GF ;

Perdreau-Remington, F .

LANCET, 2006, 367 (9512) :731-739

[14] Metabolic Footprint Analysis Uncovers Strain Specific Overflow Metabolism and D-Isoleucine Production of Staphylococcus Aureus COL and HG001 [J].

Doerries, Kirsten ;

Lalk, Michael .

PLOS ONE, 2013, 8 (12)

[15] Two glyceraldehyde-3-phosphate dehydrogenases with opposite physiological roles in a nonphotosynthetic bacterium [J].

Fillinger, S ;

Boschi-Muller, S ;

Azza, S ;

Dervyn, E ;

Branlant, G ;

Aymerich, S .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (19) :14031-14037

[16] Analysis of and function predictions for previously conserved hypothetical or putative proteins in Blochmannia floridanus -: art. no. 1 [J].

Gaudermann, P ;

Vogl, I ;

Zientz, E ;

Silva, FJ ;

Moya, A ;

Gross, R ;

Dandekar, T .

BMC MICROBIOLOGY, 2006, 6 (1)

[17] Insights on evolution of virulence and resistance from the complete genome analysis of an early methicillin-resistant Staphylococcus aureus strain and a biofilm-producing methicillin-resistant Staphylococcus epidermidis strain [J].

Gill, SR ;

Fouts, DE ;

Archer, GL ;

Mongodin, EF ;

DeBoy, RT ;

Ravel, J ;

Paulsen, IT ;

Kolonay, JF ;

Brinkac, L ;

Beanan, M ;

Dodson, RJ ;

Daugherty, SC ;

Madupu, R ;

Angiuoli, SV ;

Durkin, AS ;

Haft, DH ;

Vamathevan, J ;

Khouri, H ;

Utterback, T ;

Lee, C ;

Dimitrov, G ;

Jiang, LX ;

Qin, HY ;

Weidman, J ;

Tran, K ;

Kang, K ;

Hance, IR ;

Nelson, KE ;

Fraser, CM .

JOURNAL OF BACTERIOLOGY, 2005, 187 (07) :2426-2438

[18] Geographic Distribution of Staphylococcus aureus Causing Invasive Infections in Europe: A Molecular-Epidemiological Analysis [J].

Grundmann, Hajo ;

Aanensen, David M. ;

van den Wijngaard, Cees C. ;

Spratt, Brian G. ;

Harmsen, Dag ;

Friedrich, Alexander W. .

PLOS MEDICINE, 2010, 7 (01)

[19] The TIGRFAMs database of protein families [J].

Haft, DH ;

Selengut, JD ;

White, O .

NUCLEIC ACIDS RESEARCH, 2003, 31 (01) :371-373

[20] Repair of Global Regulators in Staphylococcus aureus 8325 and Comparative Analysis with Other Clinical Isolates [J].

Herbert, Silvia ;

Ziebandt, Anne-Kathrin ;

Ohlsen, Knut ;

Schaefer, Tina ;

Hecker, Michael ;

Albrecht, Dirk ;

Novick, Richard ;

Goetz, Friedrich .

INFECTION AND IMMUNITY, 2010, 78 (06) :2877-2889

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