title: Rational Design, Synthesis, and Preliminary Structure-Activity Relationships of α-Substituted-2-Phenylcyclopropane Carboxylic Acids as Inhibitors of Salmonella typhimurium O-Acetylserine Sulfhydrylase.
abstract: Cysteine is a building block for several biomolecules that are crucial for living organisms. The last step of cysteine biosynthesis is catalyzed by O-acetylserine sulfydrylase (OASS), a highly conserved pyridoxal 5'-phosphate (PLP)-dependent enzyme, present in different isoforms in bacteria, plants, and nematodes, but absent in mammals. Beside the biosynthesis of cysteine, OASS exerts a series of "moonlighting" activities in bacteria, such as transcriptional regulation, contact-dependent growth inhibition, swarming motility, and induction of antibiotic resistance. Therefore, the discovery of molecules capable of inhibiting OASS would be a valuable tool to unravel how this protein affects the physiology of unicellular organisms. As a continuation of our efforts toward the synthesis of OASS inhibitors, in this work we have used a combination of computational and spectroscopic approaches to rationally design, synthesize, and test a series of substituted 2-phenylcyclopropane carboxylic acids that bind to the two S. typhymurium OASS isoforms at nanomolar concentrations.
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.forename: Giannamaria
authors.initials: G
authors.lastname: Annunziato
authors.forename: Claudia
authors.initials: C
authors.lastname: Beato
authors.forename: Randy
authors.initials: R
authors.lastname: Wouters
authors.forename: Roberto
authors.initials: R
authors.lastname: Benoni
authors.forename: Barbara
authors.initials: B
authors.lastname: Campanini
authors.forename: Thelma A
authors.initials: TA
authors.lastname: Pertinhez
authors.affiliation: Department of Neurosciences, University of Parma , Via Volturno, 39, 43125 Parma, Italy.|National Institute of Biostructures and Biosystems , Viale delle Medaglie d'Oro 305, 00136 Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bettati
authors.affiliation: National Institute of Biostructures and Biosystems , Viale delle Medaglie d'Oro 305, 00136 Rome, Italy.|Institute of Biophysics, CNR , /o Area di Ricerca San Cataldo, Via G. Moruzzi N° 1, 56124 Pisa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D003547:Cysteine Synthase / Q000037:antagonists & inhibitors*; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011485:Protein Binding; D011732:Pyridoxal Phosphate / Q000737:chemistry; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D003521:Cyclopropanes; D007527:Isoenzymes; D011732:Pyridoxal Phosphate; D003547:Cysteine Synthase