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Small molecule inhibitors of peptidoglycan synthesis targeting the lipid II precursor
Derouaux, Adeline (Avtor), Turk, Samo (Avtor), Olrichs, Nick K. (Avtor), Gobec, Stanislav (Avtor), Breukink, Eefjan (Avtor), Amoroso, Ana (Avtor), Offant, Jullien (Avtor), Bostock, Julieanne M. (Avtor), Mariner, Katherine (Avtor), Chopra, Ian (Avtor), Vernet, Thierry (Avtor), Zervosen, Astrid (Avtor), Joris, Bernard (Avtor), Frère, Jean-Marie (Avtor), Nguyen-Distèche, Martine (Avtor), Terrak, Mohammed (Avtor)

URLURL - Predstavitvena datoteka, za dostop obiščite http://www.sciencedirect.com/science/journal/00062952 Novo okno

Izvleček
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.

Jezik:Angleški jezik
Ključne besede:glikoziltransferaza, peptidoglikan, lipid II, GT inhibitor
Vrsta gradiva:Delo ni kategorizirano (r6)
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2011
Št. strani:str. 1098-1105
Številčenje:Vol. 81, no. 9
UDK:542:615.2
ISSN pri članku:0006-2952
DOI:10.1016/j.bcp.2011.02.008 Povezava se odpre v novem oknu
COBISS.SI-ID:2990449 Povezava se odpre v novem oknu
Število ogledov:402
Število prenosov:207
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
 
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Gradivo je del revije

Naslov:Biochemical pharmacology
Skrajšan naslov:Biochem. pharmacol.
Založnik:Pergamon Press
ISSN:0006-2952
COBISS.SI-ID:276759 Novo okno

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