title: Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-β-Lactamases and Penicillin-Binding Proteins.
abstract: Avibactam is a diazabicyclooctane β-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with β-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important β-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC ≤ 2 μg/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both β-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens.
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: King
authors.affiliation: The Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia . 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Dustin T
authors.initials: DT
authors.lastname: King
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: French
authors.affiliation: Centre d'Etude et de Valorisation de la Diversité Microbienne (CEVDM), Département de Biologie, Faculté des Sciences, Université de Sherbrooke , Sherbrooke, Quebec, Canada J1K 2R1.
authors.forename: Eric
authors.initials: E
authors.lastname: Brouillette
authors.affiliation: Centre d'Etude et de Valorisation de la Diversité Microbienne (CEVDM), Département de Biologie, Faculté des Sciences, Université de Sherbrooke , Sherbrooke, Quebec, Canada J1K 2R1.
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Asli
authors.affiliation: The Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia . 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: J Andrew N
authors.initials: JA
authors.lastname: Alexander
authors.affiliation: The Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia . 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Marija
authors.initials: M
authors.lastname: Vuckovic
authors.affiliation: NAEJA Pharmaceutical, Inc. , Edmonton, Alberta T6E 5V2, Canada.
authors.forename: Samarendra N
authors.initials: SN
authors.lastname: Maiti
authors.affiliation: Fedora Pharmaceutical, Inc. , Edmonton, Alberta T6E 5V2, Canada.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Parr
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
authors.affiliation: Centre d'Etude et de Valorisation de la Diversité Microbienne (CEVDM), Département de Biologie, Faculté des Sciences, Université de Sherbrooke , Sherbrooke, Quebec, Canada J1K 2R1.
authors.forename: François
authors.initials: F
authors.lastname: Malouin
authors.affiliation: The Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia . 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Natalie C J
authors.initials: NC
authors.lastname: Strynadka
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
mesh_terms: D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000378:metabolism*; D011487:Protein Conformation; D065093:beta-Lactamase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D053961:Azabicyclo Compounds; D046915:Penicillin-Binding Proteins; D065093:beta-Lactamase Inhibitors