title: Target profiling of 4-hydroxyderricin in S. aureus reveals seryl-tRNA synthetase binding and inhibition by covalent modification.
abstract: 4-Hydroxyderricin is a heat labile bioactive chalcone isolated from the plant Angelica keiskei. It received attention due to its antibiotic potency against several strains of bacteria including pathogens such as Staphylococcus aureus. Despite these promising pharmacological properties, the exact mode of action or the biological targets are still unknown. Here we report the synthesis and the application of a 4-hydroxyderricin probe for activity-based protein profiling (ABPP) in S. aureus. Due to the heat sensitivity of the natural product we utilize a chemical tool for the mild and selective enrichment of labile probe-protein conjugates and report seryl-tRNA synthetase (STS) to be covalently modified by our probe. This modification results in inhibition of the amino acylation of tRNAs catalyzed by S. aureus STS which is an essential enzymatic pathway for bacterial viability.
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Lehrstuhl für organische Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Battenberg
authors.forename: Yinliang
authors.initials: Y
authors.lastname: Yang
authors.forename: Steven H L
authors.initials: SH
authors.lastname: Verhelst
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
mesh_terms: D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D002599:Chalcone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D057930:Click Chemistry; D004926:Escherichia coli; D005456:Fluorescent Dyes / Q000737:chemistry; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D012235:Rhodamines / Q000737:chemistry; D012714:Serine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D013211:Staphylococcus aureus / Q000201:enzymology*; D014297:Trimethylsilyl Compounds / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005456:Fluorescent Dyes; D012235:Rhodamines; D014297:Trimethylsilyl Compounds; C068243:4-hydroxyderricin; D002599:Chalcone; D012714:Serine-tRNA Ligase