title: Natural-Product-Inspired Aminoepoxybenzoquinones Kill Members of the Gram-Negative Pathogen Salmonella by Attenuating Cellular Stress Response.
abstract: Gram-negative bacteria represent a challenging task for antibacterial drug discovery owing to their impermeable cell membrane and restricted uptake of small molecules. We herein describe the synthesis of natural-product-derived epoxycyclohexenones and explore their antibiotic activity against several pathogenic bacteria. A compound with activity against Salmonella Typhimurium was identified, and the target enzymes were unraveled by quantitative chemical proteomics. Importantly, two protein hits were linked to bacterial stress response, and corresponding assays revealed an elevated susceptibility to reactive oxygen species upon compound treatment. The consolidated inhibition of these targets provides a rationale for antibacterial activity and highlights epoxycyclohexenones as natural product scaffolds with suitable properties for killing Gram-negative Salmonella.
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
authors: Franziska A
authors: FA
authors: Mandl
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
authors: Volker C
authors: VC
authors: Kirsch
authors: Center for Integrated Protein Science, Department für Biowissenschaften, Technische Universität München, Erlenmeyer-Forum 8, 85354, Freising, Germany.
authors: Ilke
authors: I
authors: Ugur
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
authors: Elena
authors: E
authors: Kunold
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
authors: Jan
authors: J
authors: Vomacka
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
authors: Christian
authors: C
authors: Fetzer
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
authors: Sabine
authors: S
authors: Schneider
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
authors: Klaus
authors: K
authors: Richter
authors: Lehrstuhl für Mikrobielle Ökologie, Zentralinstitut für Ernährungs- und Lebensmittelforschung, Technische Universität München, Weihenstephaner Berg 3, 85354, Freising, Germany.
authors: Thilo M
authors: TM
authors: Fuchs
authors: Center for Integrated Protein Science, Department für Biowissenschaften, Technische Universität München, Erlenmeyer-Forum 8, 85354, Freising, Germany.
authors: Iris
authors: I
authors: Antes
authors: Center for Integrated Protein Science, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.
authors: Stephan A
authors: SA
authors: Sieber
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D012486:Salmonella typhimurium / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D016227:Benzoquinones; D001688:Biological Products
keywords: Gram-negative bacteria; antibiotic resistance; covalent inhibitors; quantitative proteomics; stress response