title: Synthesis and evaluation of boronic acids as inhibitors of Penicillin Binding Proteins of classes A, B and C.
abstract: In response to the widespread use of β-lactam antibiotics bacteria have evolved drug resistance mechanisms that include the production of resistant Penicillin Binding Proteins (PBPs). Boronic acids are potent β-lactamase inhibitors and have been shown to display some specificity for soluble transpeptidases and PBPs, but their potential as inhibitors of the latter enzymes is yet to be widely explored. Recently, a (2,6-dimethoxybenzamido)methylboronic acid was identified as being a potent inhibitor of Actinomadura sp. R39 transpeptidase (IC(50): 1.3 μM). In this work, we synthesized and studied the potential of a number of acylaminomethylboronic acids as inhibitors of PBPs from different classes. Several derivatives inhibited PBPs of classes A, B and C from penicillin sensitive strains. The (2-nitrobenzamido)methylboronic acid was identified as a good inhibitor of a class A PBP (PBP1b from Streptococcus pneumoniae, IC(50) = 26 μM), a class B PBP (PBP2xR6 from Streptococcus pneumoniae, IC(50) = 138 μM) and a class C PBP (R39 from Actinomadura sp., IC(50) = 0.6 μM). This work opens new avenues towards the development of molecules that inhibit PBPs, and eventually display bactericidal effects, on distinct bacterial species.
authors.affiliation: Centre de Recherches du Cyclotron, B30, Université de Liège, Sart-Tilman, B-4000 Liège, Belgium. azervosen@ulg.ac.be
authors.forename: Astrid
authors.initials: A
authors.lastname: Zervosen
authors.forename: André
authors.initials: A
authors.lastname: Bouillez
authors.forename: Alexandre
authors.initials: A
authors.lastname: Herman
authors.forename: Ana
authors.initials: A
authors.lastname: Amoroso
authors.forename: Bernard
authors.initials: B
authors.lastname: Joris
authors.forename: Eric
authors.initials: E
authors.lastname: Sauvage
authors.forename: Paulette
authors.initials: P
authors.lastname: Charlier
authors.forename: André
authors.initials: A
authors.lastname: Luxen
mesh_terms: D000192:Actinomycetales / Q000737:chemistry; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000145:classification*; D013296:Streptococcus pneumoniae / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001897:Boronic Acids; D046915:Penicillin-Binding Proteins