ArticleMolecular biology and evolution2017
Enzyme Efficiency but Not Thermostability Drives Cefotaxime Resistance Evolution in TEM-1 β-Lactamase.
Article in Molecular biology and evolution, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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49 citing papers in PubMed, 66 citations in OpenAlex.
- Molecular evolution in light of regulatory-coding epistasis.EMBO reports · 2026Review
- Environmental and mutational modulation of collateral fitness effects informs their mechanisms.Molecular biology and evolution · 2026Article
- Reduced catalytic activity of KPC β-lactamase can increase ceftazidime resistance.Communications biology · 2026Article
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- Dynamic signature of activity-stability tradeoff in lactamase evolution.Nature communications · 2026Article
- 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
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- Article
- Idiosyncratic evolvability among single-point ribosomal mutants towards multi-aminoglycoside resistance.PLoS genetics · 2025Article
- Transition Path Sampling Based Free Energy Calculations of Evolution's Effect on Rates in β-Lactamase: The Contributions of Rapid Protein Dynamics to Rate.The journal of physical chemistry. B · 2024Article
- Understanding epistatic networks in the B1 β-lactamases through coevolutionary statistical modeling and deep mutational scanning.Nature communications · 2024Article
- Dissecting Allosteric Mutations for Antibiotic Resistance by Time-Dependent Linear Response Theory.Journal of chemical theory and computation · 2024Article
- Article
- Positive epistasis drives clavulanic acid resistance in double mutant libraries of BlaC β-lactamase.Communications biology · 2024Article
- Epistasis arises from shifting the rate-limiting step during enzyme evolution of a β-lactamase.Nature catalysis · 2024Article
- BioCARS: Synchrotron facility for probing structural dynamics of biological macromolecules.Structural dynamics (Melville, N.Y.) · 2024Article
- Epistasis and pleiotropy shape biophysical protein subspaces associated with drug resistance.Physical review. E · 2023Article
- Evolutionary druggability: leveraging low-dimensional fitness landscapes towards new metrics for antimicrobial applications.bioRxiv : the preprint server for biology · 2023Article
- Article
- Epistasis meets pleiotropy in shaping biophysical protein subspaces associated with antimicrobial resistance.bioRxiv : the preprint server for biology · 2023Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
A leading intellectual challenge in evolutionary genetics is to identify the specific phenotypes that drive adaptation. Enzymes offer a particularly promising opportunity to pursue this question, because many enzymes' contributions to organismal fitness depend on a comparatively small number of experimentally accessible properties. Moreover, on first principles the demands of enzyme thermostability stand in opposition to the demands of catalytic activity. This observation, coupled with the fact that enzymes are only marginally thermostable, motivates the widely held hypothesis that mutations conferring functional improvement require compensatory mutations to restore thermostability. Here, we explicitly test this hypothesis for the first time, using four missense mutations in TEM-1 β-lactamase that jointly increase cefotaxime Minimum Inhibitory Concentration (MIC) ∼1500-fold. First, we report enzymatic efficiency (kcat/KM) and thermostability (Tm, and thence ΔG of folding) for all combinations of these mutations. Next, we fit a quantitative model that predicts MIC as a function of kcat/KM and ΔG. While kcat/KM explains ∼54% of the variance in cefotaxime MIC (∼92% after log transformation), ΔG does not improve explanatory power of the model. We also find that cefotaxime MIC rises more slowly in kcat/KM than predicted. Several explanations for these discrepancies are suggested. Finally, we demonstrate substantial sign epistasis in MIC and kcat/KM, and antagonistic pleiotropy between phenotypes, in spite of near numerical additivity in the system. Thus constraints on selectively accessible trajectories, as well as limitations in our ability to explain such constraints in terms of underlying mechanisms are observed in a comparatively "well-behaved" system.
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