title: Small molecule inhibitors of peptidoglycan synthesis targeting the lipid II precursor.
abstract: 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.
authors.affiliation: Centre d'Ingénierie des Protéines, Université de Liège, Allée de la chimie, B6a, B-4000, Sart Tilman, Liège, Belgium.
authors.forename: Adeline
authors.initials: A
authors.lastname: Derouaux
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Nick K
authors.initials: NK
authors.lastname: Olrichs
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.forename: Ana
authors.initials: A
authors.lastname: Amoroso
authors.forename: Julien
authors.initials: J
authors.lastname: Offant
authors.forename: Julieanne
authors.initials: J
authors.lastname: Bostock
authors.forename: Katherine
authors.initials: K
authors.lastname: Mariner
authors.forename: Ian
authors.initials: I
authors.lastname: Chopra
authors.forename: Thierry
authors.initials: T
authors.lastname: Vernet
authors.forename: Astrid
authors.initials: A
authors.lastname: Zervosen
authors.forename: Bernard
authors.initials: B
authors.lastname: Joris
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Frère
authors.forename: Martine
authors.initials: M
authors.lastname: Nguyen-Distèche
authors.forename: Mohammed
authors.initials: M
authors.lastname: Terrak
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D055162:Biocatalysis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D050356:Lipid Metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010457:Peptidoglycan / Q000096:biosynthesis / Q000187:drug effects*; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010457:Peptidoglycan; D046928:Peptidoglycan Glycosyltransferase