ArticleThe Journal of biological chemistry2020
Antagonism between substitutions in β-lactamase explains a path not taken in the evolution of bacterial drug resistance.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 24 citations in OpenAlex.
- Role of extended-spectrum β-lactamase (ESBL) genes in the dissemination of β-lactam resistance within aquatic environments: mechanisms, persistence, and one health implications.World journal of microbiology & biotechnology · 2026Review
- Cefdinir binding to a class A β-lactamase revealed by serial cryo-crystallography.Acta crystallographica. Section D, Structural biology · 2026Article
- Efficient acrylamide adduct formation suggests dual applications of ReAIV L-asparaginase.Amino acids · 2026Article
- Emergence of co-resistance to imipenem/relebactam and ceftazidime/avibactam in clinicalAntimicrobial agents and chemotherapy · 2025Article
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- Intramolecular epistasis correlates with divergence of specificity in promiscuous and bifunctional NSAR/OSBS enzymes.Protein science : a publication of the Protein Society · 2025Article
- Prospective Evaluation of Structure-Based Simulations Reveal Their Ability to Predict the Impact of Kinase Mutations on Inhibitor Binding.The journal of physical chemistry. B · 2025Article
- Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding.bioRxiv : the preprint server for biology · 2025Article
- Time-resolved crystallography of boric acid binding to the active site serine of the β-lactamase CTX-M-14 and subsequent 1,2-diol esterification.Communications chemistry · 2024Article
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Slow Protein Dynamics Elicits New Enzymatic Functions by Means of Epistatic Interactions.Molecular biology and evolution · 2022Article
- Evaluation of Tebipenem Hydrolysis by β-Lactamases Prevalent in Complicated Urinary Tract Infections.Antimicrobial agents and chemotherapy · 2022Article
- Structural basis to repurpose boron-based proteasome inhibitors Bortezomib and Ixazomib as β-lactamase inhibitors.Scientific reports · 2022Article
- Mutation of the conserved Asp-Asp pair impairs the structure, function, and inhibition of CTX-M Class A β-lactamase.FEBS letters · 2021Article
- The Role of Rigid Residues in Modulating TEM-1 β-Lactamase Function and Thermostability.International journal of molecular sciences · 2021Article
- Combination of AgNPs and Domiphen is Antimicrobial Against Biofilms of Common Pathogens.International journal of nanomedicine · 2021Article
- Local interactions with the Glu166 base and the conformation of an active site loop play key roles in carbapenem hydrolysis by the KPC-2 β-lactamase.The Journal of biological chemistryArticle
- Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance.The Journal of biological chemistryArticle
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
CTX-M β-lactamases are widespread in Gram-negative bacterial pathogens and provide resistance to the cephalosporin cefotaxime but not to the related antibiotic ceftazidime. Nevertheless, variants have emerged that confer resistance to ceftazidime. Two natural mutations, causing P167S and D240G substitutions in the CTX-M enzyme, result in 10-fold increased hydrolysis of ceftazidime. Although the combination of these mutations would be predicted to increase ceftazidime hydrolysis further, the P167S/D240G combination has not been observed in a naturally occurring CTX-M variant. Here, using recombinantly expressed enzymes, minimum inhibitory concentration measurements, steady-state enzyme kinetics, and X-ray crystallography, we show that the P167S/D240G double mutant enzyme exhibits decreased ceftazidime hydrolysis, lower thermostability, and decreased protein expression levels compared with each of the single mutants, indicating negative epistasis. X-ray structures of mutant enzymes with covalently trapped ceftazidime suggested that a change of an active-site Ω-loop to an open conformation accommodates ceftazidime leading to enhanced catalysis. 10-μs molecular dynamics simulations further correlated Ω-loop opening with catalytic activity. We observed that the WT and P167S/D240G variant with acylated ceftazidime both favor a closed conformation not conducive for catalysis. In contrast, the single substitutions dramatically increased the probability of open conformations. We conclude that the antagonism is due to restricting the conformation of the Ω-loop. These results reveal the importance of conformational heterogeneity of active-site loops in controlling catalytic activity and directing evolutionary trajectories.
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