ArticleBiochemistry2010
Crystal structures of covalent complexes of β-lactam antibiotics with Escherichia coli penicillin-binding protein 5: toward an understanding of antibiotic specificity.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 60 citations in OpenAlex.
- Only time will tell: Modelling the kinetics of covalent inhibitors.British journal of pharmacology · 2026Review
- Targeting Bacterial Cell Wall Synthesis: Structural Insights and Emerging Therapeutic Strategies.Pharmaceutics · 2026Review
- Multifaceted Small Molecules as Enzyme Modulators: Cases of Drug Discovery/Repurposing Illustrating Nature's Pragmatism.BioMed research international · 2026Review
- Binding mode of Isoxazolyl Penicillins to a Class-A β-lactamase at ambient conditions.Communications chemistry · 2025Article
- Phytochemical screening, antioxidant, and antimicrobial analysis of Portulaca oleracea seeds with in-silico molecular docking insights.Journal, genetic engineering & biotechnology · 2025Article
- Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Pilot-Scale Screening of Clinically Approved Drugs to Identify Uridine Insertion/Deletion RNA Editing Inhibitors inACS infectious diseases · 2024Article
- Comparative Modeling and Analysis of Extremophilic D-Ala-D-Ala Carboxypeptidases.Biomolecules · 2023Article
- Article
- Advances in covalent drug discovery.Nature reviews. Drug discovery · 2022Review
- Albumin grafted coaxial electrosparyed polycaprolactone-zinc oxide nanoparticle for sustained release and activity enhanced antibacterial drug delivery.RSC advances · 2022Article
- PBP4-mediated β-lactam resistance among clinical strains of Staphylococcus aureus.The Journal of antimicrobial chemotherapy · 2021Article
- β-Lactams against the Fortress of the Gram-PositiveChemical reviews · 2021Review
- Correlating Drug-Target Residence Time and Post-antibiotic Effect: Insight into Target Vulnerability.ACS infectious diseases · 2020Article
- Small-molecule covalent bond formation at tyrosine creates a binding site and inhibits activation of Ral GTPases.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli.Nature communications · 2019Article
- Structural and kinetic analyses of penicillin-binding protein 4 (PBP4)-mediated antibiotic resistance inThe Journal of biological chemistry · 2018Article
- Crystal Structures of Penicillin-Binding Protein D2 from Listeria monocytogenes and Structural Basis for Antibiotic Specificity.Antimicrobial agents and chemotherapy · 2018Article
- Optimization of a β-Lactam Scaffold for Antibacterial Activity via the Inhibition of Bacterial Type I Signal Peptidase.ACS medicinal chemistry letters · 2018Article
- Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Penicillin-binding proteins (PBPs) are the molecular targets for the widely used β-lactam class of antibiotics, but how these compounds act at the molecular level is not fully understood. We have determined crystal structures of Escherichia coli PBP 5 as covalent complexes with imipenem, cloxacillin, and cefoxitin. These antibiotics exhibit very different second-order rates of acylation for the enzyme. In all three structures, there is excellent electron density for the central portion of the β-lactam, but weak or absent density for the R1 or R2 side chains. Areas of contact between the antibiotics and PBP 5 do not correlate with the rates of acylation. The same is true for conformational changes, because although a shift of a loop leading to an electrostatic interaction between Arg248 and the β-lactam carboxylate, which occurs completely with cefoxitin and partially with imipenem and is absent with cloxacillin, is consistent with the different rates of acylation, mutagenesis of Arg248 decreased the level of cefoxitin acylation only 2-fold. Together, these data suggest that structures of postcovalent complexes of PBP 5 are unlikely to be useful vehicles for the design of new covalent inhibitors of PBPs. Finally, superimposition of the imipenem-acylated complex with PBP 5 in complex with a boronic acid peptidomimetic shows that the position corresponding to the hydrolytic water molecule is occluded by the ring nitrogen of the β-lactam. Because the ring nitrogen occupies a similar position in all three complexes, this supports the hypothesis that deacylation is blocked by the continued presence of the leaving group after opening of the β-lactam ring.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.