title: Identification of active-site inhibitors of MurG using a generalizable, high-throughput glycosyltransferase screen.
abstract: MurG is a glycosyltransferase involved in the biosynthesis of bacterial peptidoglycan. It is a potentially important antibiotic target, but no inhibitors of the enzyme have been reported. In general, inhibitors of glycosyltransferases have been difficult to design. Furthermore, no glycosyltransferase inhibitors have been identified through high-throughput screening, perhaps because appropriate screens for glycosyltransferase inhibition have not been developed. In this manuscript, we describe the development of a high-throughput screen for MurG that was used to screen a 50 000 compound library for inhibitors. The screen, which can be generalized to other glycosyltransferases, led to the identification of a family of active-site directed MurG inhibitors. The family of inhibitors contains a five-membered heterocyclic core that appears to function as a diphosphate mimic with respect to the presentation of substituents. We discuss the implications of this result and the utility of the screen for identifying inhibitors of other glycosyltransferases.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Jeremiah S
authors.initials: JS
authors.lastname: Helm
authors.forename: Yanan
authors.initials: Y
authors.lastname: Hu
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.forename: Ben
authors.initials: B
authors.lastname: Gross
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D004791:Enzyme Inhibitors; D016695:Glycosyltransferases; D017351:N-Acetylglucosaminyltransferases; C064057:UDP-N-acetylglucosamine-N-acetylmuramyl-(pentapeptide)pyrophosphoryl-undecaprenol N-acetylglucosamine transferase