ArticleThe Journal of biological chemistry2009
Crystal structures of penicillin-binding protein 2 from penicillin-susceptible and -resistant strains of Neisseria gonorrhoeae reveal an unexpectedly subtle mechanism for antibiotic resistance.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 92 citations in OpenAlex.
- Article
- Antibiotic-resistance mutations in penicillin-binding protein 2 from the ceftriaxone-resistantbioRxiv : the preprint server for biology · 2025Article
- Machine learning-based virtual screening and density functional theory characterisation of natural inhibitors targeting mutant PBP2x in Streptococcus pneumoniae.Scientific reports · 2025Article
- Molecular Detection of Mutations in theTropical medicine and infectious disease · 2025Article
- Computational and Experimental Study of Metal-Organic Frameworks (MOFs) as Antimicrobial Agents againstACS applied materials & interfaces · 2025Article
- Cefotaxime-Resistant Neisseria meningitidis Sequence Type 4821 Causing Fulminant Meningitis.Emerging infectious diseases · 2025Article
- Differential contribution of PBP occupancy and efflux on the effectiveness of β-lactams at their target site in clinical isolates of Neisseria gonorrhoeae.PLoS pathogens · 2024Article
- Rolling the evolutionary dice:Microbiology spectrum · 2024Article
- Investigation into the Interaction between Penicillin-Resistant and Penicillin-Susceptible Gonococcal Penicillin-Binding Protein 2 and Target Phenolic Ligands through Molecular Docking Studies and Structure-Activity Relationship Analysis.Advances in pharmacological and pharmaceutical sciences · 2024Article
- Molecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5.Nature communications · 2023Article
- Recent Evolution of Susceptibility to Beta-Lactams inAntibiotics (Basel, Switzerland) · 2023Article
- Evolution of Ceftriaxone Resistance of Penicillin-Binding Proteins 2 Revealed by Molecular Modeling.International journal of molecular sciences · 2022Article
- Molecular Mechanisms of Drug Resistance and Epidemiology of Multidrug-Resistant Variants ofInternational journal of molecular sciences · 2022Review
- Article
- Article
- In Silico and In Vitro Evaluation of the Antimicrobial Potential ofAntibiotics (Basel, Switzerland) · 2021Article
- Multidrug-resistant Neisseria gonorrhoeae infection in heterosexual men with reduced susceptibility to ceftriaxone, first report in Thailand.Scientific reports · 2021Article
- Molecular Typing ofPathogens (Basel, Switzerland) · 2020Article
- The frontiers of addressing antibiotic resistance in Neisseria gonorrhoeae.Translational research : the journal of laboratory and clinical medicine · 2020Review
- Mutations in penicillin-binding protein 2 from cephalosporin-resistantThe Journal of biological chemistry · 2020Article
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 1 country.
Funding
Abstract
Penicillin-binding protein 2 (PBP2) from N. gonorrhoeae is the major molecular target for beta-lactam antibiotics used to treat gonococcal infections. PBP2 from penicillin-resistant strains of N. gonorrhoeae harbors an aspartate insertion after position 345 (Asp-345a) and 4-8 additional mutations, but how these alter the architecture of the protein is unknown. We have determined the crystal structure of PBP2 derived from the penicillin-susceptible strain FA19, which shows that the likely effect of Asp-345a is to alter a hydrogen-bonding network involving Asp-346 and the SXN triad at the active site. We have also solved the crystal structure of PBP2 derived from the penicillin-resistant strain FA6140 that contains four mutations near the C terminus of the protein. Although these mutations lower the second order rate of acylation for penicillin by 5-fold relative to wild type, comparison of the two structures shows only minor structural differences, with the positions of the conserved residues in the active site essentially the same in both. Kinetic analyses indicate that two mutations, P551S and F504L, are mainly responsible for the decrease in acylation rate. Melting curves show that the four mutations lower the thermal stability of the enzyme. Overall, these data suggest that the molecular mechanism underlying antibiotic resistance contributed by the four mutations is subtle and involves a small but measurable disordering of residues in the active site region that either restricts the binding of antibiotic or impedes conformational changes that are required for acylation by beta-lactam antibiotics.
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