ArticleBiochemistry2017
The Drug-Resistant Variant P167S Expands the Substrate Profile of CTX-M β-Lactamases for Oxyimino-Cephalosporin Antibiotics by Enlarging the Active Site upon Acylation.
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 29 citations in OpenAlex.
- Cefdinir binding to a class A β-lactamase revealed by serial cryo-crystallography.Acta crystallographica. Section D, Structural biology · 2026Article
- Molecular Epidemiology of Extended-spectrum β-Lactamase-producingAnnals of laboratory medicine · 2026Article
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Evolution of ceftazidime/avibactam resistance and plasmid dynamics in OXA-48-producing Klebsiella spp. during long-term patient colonization.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2025Article
- Antibiotic susceptibility of clinicalAntimicrobial agents and chemotherapy · 2023Article
- Mapping the determinants of catalysis and substrate specificity of the antibiotic resistance enzyme CTX-M β-lactamase.Communications biology · 2023Article
- An active site loop toggles between conformations to control antibiotic hydrolysis and inhibition potency for CTX-M β-lactamase drug-resistance enzymes.Nature communications · 2022Article
- Slow Protein Dynamics Elicits New Enzymatic Functions by Means of Epistatic Interactions.Molecular biology and evolution · 2022Article
- Article
- Functional Dynamics of Substrate Recognition in TEM Beta-Lactamase.Entropy (Basel, Switzerland) · 2022Article
- Prediction of Antibiotic Resistance Evolution by Growth Measurement of All Proximal Mutants of Beta-Lactamase.Molecular biology and evolution · 2022Article
- β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates.RSC medicinal chemistry · 2021Review
- Toho-1 β-lactamase: backbone chemical shift assignments and changes in dynamics upon binding with avibactam.Journal of biomolecular NMR · 2021Article
- A drug-resistant β-lactamase variant changes the conformation of its active-site proton shuttle to alter substrate specificity and inhibitor potency.The Journal of biological chemistry · 2020Article
- Molecular Mechanisms, Epidemiology, and Clinical Importance of β-Lactam Resistance inInternational journal of molecular sciences · 2020Review
- Antagonism between substitutions in β-lactamase explains a path not taken in the evolution of bacterial drug resistance.The Journal of biological chemistry · 2020Article
- Non-catalytic-Region Mutations Conferring Transition of Class A β-Lactamases Into ESBLs.Frontiers in molecular biosciences · 2020Article
- Synergistic effects of functionally distinct substitutions in β-lactamase variants shed light on the evolution of bacterial drug resistance.The Journal of biological chemistry · 2018Article
- Megahertz serial crystallography.Nature communications · 2018Article
- Structural and Mechanistic Basis for Extended-Spectrum Drug-Resistance Mutations in Altering the Specificity of TEM, CTX-M, and KPC β-lactamases.Frontiers in molecular biosciences · 2018Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
CTX-M β-lactamases provide resistance against the β-lactam antibiotic, cefotaxime, but not a related antibiotic, ceftazidime. β-Lactamases that carry the P167S substitution, however, provide ceftazidime resistance. In this study, CTX-M-14 was used as a model to study the structural changes caused by the P167S mutation that accelerate ceftazidime turnover. X-ray crystallography was used to determine the structures of the P167S apoenzyme along with the structures of the S70G/P167S, E166A/P167S, and E166A mutant enzymes complexed with ceftazidime as well as the E166A/P167S apoenzyme. The S70G and E166A mutations allow capture of the enzyme-substrate complex and the acylated form of ceftazidime, respectively. The results showed a large conformational change in the Ω-loop of the ceftazidime acyl-enzyme complex of the P167S mutant but not in the enzyme-substrate complex, suggesting the change occurs upon acylation. The change results in a larger active site that prevents steric clash between the aminothiazole ring of ceftazidime and the Asn170 residue in the Ω-loop, allowing accommodation of ceftazidime for hydrolysis. In addition, the conformational change was not observed in the E166A/P167S apoenzyme, suggesting the presence of acylated ceftazidime influences the conformational change. Finally, the E166A acyl-enzyme structure with ceftazidime did not exhibit the altered conformation, indicating the P167S substitution is required for the change. Taken together, the results reveal that the P167S substitution and the presence of acylated ceftazidime both drive the structure toward a conformational change in the Ω-loop and that in CTX-M P167S enzymes found in drug-resistant bacteria this will lead to an increased level of ceftazidime hydrolysis.
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