Reference : Small molecule inhibitors of peptidoglycan synthesis targeting the lipid II precursor.
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/94677
Small molecule inhibitors of peptidoglycan synthesis targeting the lipid II precursor.
English
Derouaux, Adeline mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Turk, Samo [> > > >]
Olrichs, Nick K [> > > >]
Gobec, Stanislav [> > > >]
Breukink, Eefjan [> > > >]
Amoroso, Ana Maria mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Offant, Julien [> > > >]
Bostock, Julieanne [> > > >]
Mariner, Katherine [> > > >]
Chopra, Ian [> > > >]
Vernet, Thierry [> > > >]
Zervosen, Astrid mailto [Université de Liège - ULg > > Centre de recherches du cyclotron >]
Joris, Bernard mailto [Université de Liège - ULg > Département des sciences de la vie > Physiologie et génétique bactériennes >]
Frère, Jean-Marie mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Nguyen Van, Martine mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Terrak, Mohammed mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
2011
Biochemical Pharmacology
Elsevier Science
81
9
1098-105
Yes (verified by ORBi)
International
0006-2952
Oxford
United Kingdom
[en] Anti-Bacterial Agents/chemistry/pharmacology ; Biocatalysis ; Enzyme Inhibitors/chemistry/pharmacology ; Lipid Metabolism ; Microbial Sensitivity Tests ; Models, Molecular ; Peptidoglycan/biosynthesis/drug effects ; Peptidoglycan Glycosyltransferase/antagonists & inhibitors
[en] Bacterial peptidoglycan glycosyltransferases (GTs) of family 51 catalyze the polymerization of the lipid II precursor into linear peptidoglycan strands. This activity is essential to bacteria and represents a validated target for the development of new antibacterials. Application of structure-based virtual screening to the National Cancer Institute library using eHits program and the structure of the glycosyltransferase domain of the Staphylococcus aureus penicillin-binding protein 2 resulted in the identification of two small molecules analogues 5, a 2-[1-[(2-chlorophenyl)methyl]-2-methyl-5-methylsulfanylindol-3-yl]ethanamine and 5b, a 2-[1-[(3,4-dichlorophenyl)methyl]-2-methyl-5-methylsulfanylindol-3-yl]ethanamine that exhibit antibacterial activity against several Gram-positive bacteria but were less active on Gram-negative bacteria. The two compounds inhibit the activity of five GTs in the micromolar range. Investigation of the mechanism of action shows that the compounds specifically target peptidoglycan synthesis. Unexpectedly, despite the fact that the compounds were predicted to bind to the GT active site, compound 5b was found to interact with the lipid II substrate via the pyrophosphate motif. In addition, this compound showed a negatively charged phospholipid-dependent membrane depolarization and disruption activity. These small molecules are promising leads for the development of more active and specific compounds to target the essential GT step in cell wall synthesis.
Researchers ; Professionals
http://hdl.handle.net/2268/94677
also: http://hdl.handle.net/2268/108852
10.1016/j.bcp.2011.02.008
Copyright (c) 2011 Elsevier Inc. All rights reserved.

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