ArticlePLoS genetics2012
Quantifying the adaptive potential of an antibiotic resistance enzyme.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 109 citations in OpenAlex.
- Mutation-biased adaptation is consequential even in large bacterial populations.Nature communications · 2026Article
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- Article
- The distribution of fitness effects during adaptive walks using a simple genetic network.PLoS genetics · 2024Article
- Molecular Mechanisms and the Significance of Synonymous Mutations.Biomolecules · 2024Review
- Quantifying stochastic establishment of mutants in microbial adaptation.Microbiology (Reading, England) · 2023Review
- Article
- The High Mutational Sensitivity of ccdA Antitoxin Is Linked to Codon Optimality.Molecular biology and evolution · 2022Article
- Unpredictable repeatability in molecular evolution.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Fitness of evolving bacterial populations is contingent on deep and shallow history but only shallow history creates predictable patterns.Proceedings. Biological sciences · 2022Article
- Stochastic establishment of β-lactam-resistantProceedings. Biological sciences · 2022Article
- Population size mediates the contribution of high-rate and large-benefit mutations to parallel evolution.Nature ecology & evolution · 2022Article
- Revisiting Antibiotic Resistance: Mechanistic Foundations to Evolutionary Outlook.Antibiotics (Basel, Switzerland) · 2021Review
- Forecasting of phenotypic and genetic outcomes of experimental evolution in Pseudomonas protegens.PLoS genetics · 2021Article
- Historical Contingency Causes Divergence in Adaptive Expression of the lac Operon.Molecular biology and evolution · 2021Article
- Role of Synonymous Mutations in the Evolution of TEM β-Lactamase Genes.Antimicrobial agents and chemotherapy · 2021Article
- Adaptive Processes Change as Multiple Functions Evolve.Antimicrobial agents and chemotherapy · 2021Article
- Antibiotic Breakdown by Susceptible Bacteria Enhances the Establishment of β-Lactam Resistant Mutants.Frontiers in microbiology · 2021Article
- Stochastic bacterial population dynamics restrict the establishment of antibiotic resistance from single cells.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Stochastic Gene Expression Influences the Selection of Antibiotic Resistance Mutations.Molecular biology and evolution · 2020Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
For a quantitative understanding of the process of adaptation, we need to understand its "raw material," that is, the frequency and fitness effects of beneficial mutations. At present, most empirical evidence suggests an exponential distribution of fitness effects of beneficial mutations, as predicted for Gumbel-domain distributions by extreme value theory. Here, we study the distribution of mutation effects on cefotaxime (Ctx) resistance and fitness of 48 unique beneficial mutations in the bacterial enzyme TEM-1 β-lactamase, which were obtained by screening the products of random mutagenesis for increased Ctx resistance. Our contributions are threefold. First, based on the frequency of unique mutations among more than 300 sequenced isolates and correcting for mutation bias, we conservatively estimate that the total number of first-step mutations that increase Ctx resistance in this enzyme is 87 [95% CI 75-189], or 3.4% of all 2,583 possible base-pair substitutions. Of the 48 mutations, 10 are synonymous and the majority of the 38 non-synonymous mutations occur in the pocket surrounding the catalytic site. Second, we estimate the effects of the mutations on Ctx resistance by determining survival at various Ctx concentrations, and we derive their fitness effects by modeling reproduction and survival as a branching process. Third, we find that the distribution of both measures follows a Fréchet-type distribution characterized by a broad tail of a few exceptionally fit mutants. Such distributions have fundamental evolutionary implications, including an increased predictability of evolution, and may provide a partial explanation for recent observations of striking parallel evolution of antibiotic resistance.
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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.