ArticlePloS one2013
Directed evolution of Mycobacterium tuberculosis β-lactamase reveals gatekeeper residue that regulates antibiotic resistance and catalytic efficiency.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
- Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.Protein science : a publication of the Protein Society · 2025Article
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
- Conserved proline residues prevent dimerization and aggregation in the β-lactamase BlaC.Protein science : a publication of the Protein Society · 2024Article
- Positive epistasis drives clavulanic acid resistance in double mutant libraries of BlaC β-lactamase.Communications biology · 2024Article
- Mycobacterium tuberculosis β-lactamase variant reduces sensitivity to ampicillin/avibactam in a zebrafish-Mycobacterium marinum model of tuberculosis.Scientific reports · 2023Article
- Heterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam.Nature communications · 2023Article
- A primer to directed evolution: current methodologies and future directions.RSC chemical biology · 2023Review
- Heterogeneity in the M. tuberculosis β-Lactamase Inhibition by Sulbactam.Research square · 2023Article
- The roles of highly conserved, non-catalytic residues in class A β-lactamases.Protein science : a publication of the Protein Society · 2022Article
- The G132S Mutation Enhances the Resistance ofBiochemistry · 2021Article
- Two β-Lactamase Variants with Reduced Clavulanic Acid Inhibition Display Different Millisecond Dynamics.Antimicrobial agents and chemotherapy · 2021Article
- Tetracycline-inactivating enzymes from environmental, human commensal, and pathogenic bacteria cause broad-spectrum tetracycline resistance.Communications biology · 2020Article
- New Conformations of Acylation Adducts of Inhibitors of β-Lactamase from Mycobacterium tuberculosis.Biochemistry · 2019Article
- Molecular docking and dynamics of Nickel-Schiff base complexes for inhibiting β-lactamase ofIn silico pharmacology · 2018Article
- Phosphate Promotes the Recovery of Mycobacterium tuberculosis β-Lactamase from Clavulanic Acid Inhibition.Biochemistry · 2017Article
- Structural enzymology using X-ray free electron lasers.Structural dynamics (Melville, N.Y.) · 2017Article
- Engineering Nucleotide Specificity of Succinyl-CoA Synthetase in Blastocystis: The Emerging Role of Gatekeeper Residues.Biochemistry · 2017Article
- β-Lactam Resistance Mechanisms: Gram-Positive Bacteria and Mycobacterium tuberculosis.Cold Spring Harbor perspectives in medicine · 2016Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Directed evolution can be a powerful tool for revealing the mutational pathways that lead to more resistant bacterial strains. In this study, we focused on the bacterium Mycobacterium tuberculosis, which is resistant to members of the β-lactam class of antibiotics and thus continues to pose a major public health threat. Resistance of this organism is the result of a chromosomally encoded, extended spectrum class A β-lactamase, BlaC, that is constitutively produced. Here, combinatorial enzyme libraries were selected on ampicillin to identify mutations that increased resistance of bacteria to β-lactams. After just a single round of mutagenesis and selection, BlaC mutants were evolved that conferred 5-fold greater antibiotic resistance to cells and enhanced the catalytic efficiency of BlaC by 3-fold compared to the wild-type enzyme. All isolated mutants carried a mutation at position 105 (e.g., I105F) that appears to widen access to the active site by 3.6 Å while also stabilizing the reorganized topology. In light of these findings, we propose that I105 is a 'gatekeeper' residue of the active site that regulates substrate hydrolysis by BlaC. Moreover, our results suggest that directed evolution can provide insight into the development of highly drug resistant microorganisms.
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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.