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Structural Insights into Ceftobiprole Inhibition of Pseudomonas aeruginosa Penicillin-Binding Protein 3.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2020 Apr 21; Vol. 64 (5). Date of Electronic Publication: 2020 Apr 21 (Print Publication: 2020). - Publication Year :
- 2020
-
Abstract
- Ceftobiprole is an advanced-generation broad-spectrum cephalosporin antibiotic with potent and rapid bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus , as well as susceptible Gram-negative pathogens, including Pseudomonas sp. pathogens. In the case of Pseudomonas aeruginosa , ceftobiprole acts by inhibiting P. aeruginosa penicillin-binding protein 3 (PBP3). Structural studies were pursued to elucidate the molecular details of this PBP inhibition. The crystal structure of the His-tagged PBP3-ceftobiprole complex revealed a covalent bond between the ligand and the catalytic residue S294. Ceftobiprole binding leads to large active site changes near binding sites for the pyrrolidinone and pyrrolidine rings. The S528 to L536 region adopts a conformation previously not observed in PBP3, including partial unwinding of the α11 helix. These molecular insights can lead to a deeper understanding of β-lactam-PBP interactions that result in major changes in protein structure, as well as suggesting how to fine-tune current inhibitors and to develop novel inhibitors of this PBP.<br /> (Copyright © 2020 American Society for Microbiology.)
- Subjects :
- Anti-Bacterial Agents metabolism
Binding Sites physiology
Catalytic Domain drug effects
Cephalosporins pharmacology
Crystallography, X-Ray
Humans
Methicillin-Resistant Staphylococcus aureus drug effects
Microbial Sensitivity Tests
Molecular Conformation
Protein Binding
Anti-Bacterial Agents pharmacology
Cephalosporins metabolism
Penicillin-Binding Proteins antagonists & inhibitors
Penicillin-Binding Proteins metabolism
Pseudomonas aeruginosa drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 64
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 32152075
- Full Text :
- https://doi.org/10.1128/AAC.00106-20