ArticleAntimicrobial agents and chemotherapy2015
Characterization of the global stabilizing substitution A77V and its role in the evolution of CTX-M β-lactamases.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Molecular and Microbiological Characteristics of UropathogenicAnnals of laboratory medicine · 2026Article
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
- 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
- Enzyme Inhibitors: The Best Strategy to Tackle Superbug NDM-1 and Its Variants.International journal of molecular sciences · 2021Review
- Article
- Molecular Mechanisms, Epidemiology, and Clinical Importance of β-Lactam Resistance inInternational journal of molecular sciences · 2020Review
- Tailored Antibacterials and Innovative Laboratories for Phage (Φ) Research: Personalized Infectious Disease Medicine for the Most Vulnerable At-Risk Patients.PHAGE (New Rochelle, N.Y.) · 2020Article
- Antagonism between substitutions in β-lactamase explains a path not taken in the evolution of bacterial drug resistance.The Journal of biological chemistry · 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
- Evolution of New Delhi metallo-β-lactamase (NDM) in the clinic: Effects of NDM mutations on stability, zinc affinity, and mono-zinc activity.The Journal of biological chemistry · 2018Article
- Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis.Antimicrobial agents and chemotherapy · 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
- 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.Biochemistry · 2017Article
- Enzyme Efficiency but Not Thermostability Drives Cefotaxime Resistance Evolution in TEM-1 β-Lactamase.Molecular biology and evolution · 2017Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
The widespread use of oxyimino-cephalosporin antibiotics drives the evolution of the CTX-M family of β-lactamases that hydrolyze these drugs and confer antibiotic resistance. Clinically isolated CTX-M enzymes carrying the P167S or D240G active site-associated adaptive mutation have a broadened substrate profile that includes the oxyimino-cephalosporin antibiotic ceftazidime. The D240G substitution is known to reduce the stability of CTX-M-14 β-lactamase, and the P167S substitution is shown here to also destabilize the enzyme. Proteins are marginally stable entities, and second-site mutations that stabilize the enzyme can offset a loss in stability caused by mutations that enhance enzyme activity. Therefore, the evolution of antibiotic resistance enzymes can be dependent on the acquisition of stabilizing mutations. The A77V substitution is present in CTX-M extended-spectrum β-lactamases (ESBLs) from a number of clinical isolates, suggesting that it may be important in the evolution of antibiotic resistance in this family of β-lactamases. In this study, the effects of the A77V substitution in the CTX-M-14 model enzyme were characterized with regard to the kinetic parameters for antibiotic hydrolysis as well as enzyme expression levels in vivo and protein stability in vitro. The A77V substitution has little effect on the kinetics of oxyimino-cephalosporin hydrolysis, but it stabilizes the CTX-M enzyme and compensates for the loss of stability resulting from the P167S and D240G mutations. The acquisition of global stabilizing mutations, such as A77V, is an important feature in β-lactamase evolution and a common mechanism in protein evolution.
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