title: Bicyclic enol cyclocarbamates inhibit penicillin-binding proteins.
abstract: Natural products form attractive leads for the development of chemical probes and drugs. The antibacterial lipopeptide Brabantamide A contains an unusual enol cyclocarbamate and we used this scaffold as inspiration for the synthesis of a panel of enol cyclocarbamate containing compounds. By equipping the scaffold with different groups, we identified structural features that are essential for antibacterial activity. Some of the derivatives block incorporation of hydroxycoumarin carboxylic acid-amino d-alanine into the newly synthesized peptidoglycan. Activity-based protein-profiling experiments revealed that the enol carbamates inhibit a specific subset of penicillin-binding proteins in B. subtilis and S. pneumoniae.
authors.affiliation: Chemical Biology, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands. m.d.witte@rug.nl.
authors.forename: Paul
authors.initials: P
authors.lastname: Dockerty
authors.affiliation: Chemical Biology, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands. m.d.witte@rug.nl.
authors.forename: Jerre G
authors.initials: JG
authors.lastname: Edens
authors.affiliation: Molecular Microbiology, Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
authors.forename: Menno B
authors.initials: MB
authors.lastname: Tol
authors.affiliation: Molecular Microbiology, Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
authors.forename: Danae
authors.initials: D
authors.lastname: Morales Angeles
authors.affiliation: Molecular Genetics, Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
authors.forename: Arnau
authors.initials: A
authors.lastname: Domenech
authors.affiliation: Chemical Biology, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands. m.d.witte@rug.nl.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Chemical Biology, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands. m.d.witte@rug.nl.
authors.forename: Anna K H
authors.initials: AK
authors.lastname: Hirsch
authors.affiliation: Molecular Genetics, Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Veening
authors.affiliation: Molecular Microbiology, Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
authors.forename: Dirk-Jan
authors.identifier: http://orcid.org/0000-0002-9439-9168
authors.initials: DJ
authors.lastname: Scheffers
authors.affiliation: Chemical Biology, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands. m.d.witte@rug.nl.
authors.forename: Martin D
authors.identifier: http://orcid.org/0000-0003-4660-2974
authors.initials: MD
authors.lastname: Witte
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors*; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001643:Bridged Bicyclo Compounds; D002219:Carbamates; D007659:Ketones; D046915:Penicillin-Binding Proteins