title: Synthesis of modified peptidoglycan precursor analogues for the inhibition of glycosyltransferase.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, University of Leuven, Belgium.
authors.forename: Shrinivas
authors.initials: S
authors.lastname: Dumbre
authors.forename: Adeline
authors.initials: A
authors.lastname: Derouaux
authors.forename: Eveline
authors.initials: E
authors.lastname: Lescrinier
authors.forename: André
authors.initials: A
authors.lastname: Piette
authors.forename: Bernard
authors.initials: B
authors.lastname: Joris
authors.forename: Mohammed
authors.initials: M
authors.lastname: Terrak
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D008968:Molecular Conformation; D010457:Peptidoglycan / Q000737:chemistry / Q000494:pharmacology*; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010457:Peptidoglycan; D046928:Peptidoglycan Glycosyltransferase