Synthesis of Modified Peptidoglycan Precursor Analogues for the Inhibition of Glycosyltransferase.

[en] The peptidoglycan glycosyltransferases (GTs) are essential enzymes that catalyze the polymerization of glycan chains of the bacterial cell wall from lipid II and thus constitute a validated antibacterial target. Their enzymatic cavity is composed of a donor site for the growing glycan chain (where the inhibitor moenomycin binds) and an acceptor site for lipid II substrate. In order to find lead inhibitors able to fill this large active site, we have synthesized a series of substrate analogues of lipid I and lipid II with variations in the lipid, the pyrophosphate, and the peptide moieties and evaluated their biological effect on the GT activity of E. coli PBP1b and their antibacterial potential. We found several compounds able to inhibit the GT activity in vitro and cause growth defect in Bacillus subtilis . The more active was C16-phosphoglycerate-MurNAc-(l-Ala-d-Glu)-GlcNAc, which also showed antibacterial activity. These molecules are promising leads for the design of new antibacterial GT inhibitors.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Dumbre, Shrinivas

Derouaux, Adeline ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Lescrinier, Eveline

Piette, André

Joris, Bernard ; Université de Liège - ULiège > Département des sciences de la vie > Physiologie et génétique bactériennes

Terrak, Mohammed ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Herdewijn, Piet

Language :

English

Title :

Synthesis of Modified Peptidoglycan Precursor Analogues for the Inhibition of Glycosyltransferase.

Publication date :

2012

Journal title :

Journal of the American Chemical Society

ISSN :

0002-7863

eISSN :

1520-5126

Publisher :

American Chemical Society, Washington, United States - District of Columbia

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 04 June 2012

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