ArticlePloS one2012
Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- 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
- Evolutionary Dynamics and Functional Differences in Clinically Relevant Pen β-Lactamases fromJournal of chemical information and modeling · 2025Article
- Exploring complexity of class-A Beta-lactamase family using physiochemical-based multiplex networks.Scientific reports · 2023Article
- Article
- Mutations in ArgS Arginine-tRNA Synthetase Confer Additional Antibiotic Tolerance Protection to Extended-Spectrum-β-Lactamase-Producing Burkholderia thailandensis.Antimicrobial agents and chemotherapy · 2020Article
- Non-catalytic-Region Mutations Conferring Transition of Class A β-Lactamases Into ESBLs.Frontiers in molecular biosciences · 2020Article
- Sequence heterogeneity of the PenA carbapenemase in clinical isolates of Burkholderia multivorans.Diagnostic microbiology and infectious disease · 2018Article
- Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance.Scientific reports · 2018Article
- Antibiotic Resistance Markers in Burkholderia pseudomallei Strain Bp1651 Identified by Genome Sequence Analysis.Antimicrobial agents and chemotherapy · 2017Article
- A potent synthetic inorganic antibiotic with activity against drug-resistant pathogens.Scientific reports · 2017Article
- Exploring the Role of the Ω-Loop in the Evolution of Ceftazidime Resistance in the PenA β-Lactamase from Burkholderia multivorans, an Important Cystic Fibrosis Pathogen.Antimicrobial agents and chemotherapy · 2017Article
- High adaptability of the omega loop underlies the substrate-spectrum-extension evolution of a class A β-lactamase, PenL.Scientific reports · 2016Article
- Antibiotic resistance in Burkholderia species.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2016Review
- Structural and Functional Aspects of Class A Carbapenemases.Current drug targets · 2016Review
- A Structure-Based Classification of Class A β-Lactamases, a Broadly Diverse Family of Enzymes.Clinical microbiology reviews · 2016Review
- Cell Wall Recycling-Linked Coregulation of AmpC and PenB β-Lactamases through ampD Mutations in Burkholderia cenocepacia.Antimicrobial agents and chemotherapy · 2015Article
- Activity of ceftazidime/avibactam against isogenic strains of Escherichia coli containing KPC and SHV β-lactamases with single amino acid substitutions in the Ω-loop.The Journal of antimicrobial chemotherapy · 2015Article
- Deletion mutations conferring substrate spectrum extension in the class A β-lactamase.Antimicrobial agents and chemotherapy · 2014Article
- The tandem repeats enabling reversible switching between the two phases of β-lactamase substrate spectrum.PLoS genetics · 2014Article
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Authors and funding
6 authors.
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No grant is acknowledged in the PubMed record.
Abstract
The continuous evolution of β-lactamases resulting in bacterial resistance to β-lactam antibiotics is a major concern in public health, and yet the underlying molecular basis or the pattern of such evolution is largely unknown. We investigated the mechanics of the substrate fspectrum expansion of the class A β-lactamase using PenA of Burkholderia thailandensis as a model. By analyzing 516 mutated enzymes that acquired the ceftazidime-hydrolyzing activity, we found twelve positions with single amino acid substitutions (altogether twenty-nine different substitutions), co-localized at the active-site pocket area. The ceftazidime MIC (minimum inhibitory concentration) levels and the relative frequency in the occurrence of substitutions did not correlate well with each other, and the latter appeared be largely influenced by the intrinsic mutational biases present in bacteria. Simulation studies suggested that all substitutions caused a congruent effect, expanding the space in a conserved structure called the omega loop, which in turn increased flexibility at the active site. A second phase of selection, in which the mutants were placed under increased antibiotic pressure, did not result in a second mutation in the coding region, but a mutation that increased gene expression arose in the promoter. This result suggests that the twelve amino acid positions and their specific substitutions in PenA may represent a comprehensive repertoire of the enzyme's adaptability to a new substrate. These mapped substitutions represent a comprehensive set of general mechanical paths to substrate spectrum expansion in class A β-lactamases that all share a functional evolutionary mechanism using common conserved residues.
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