ArticleEvolutionary applications2015
Role of pleiotropy during adaptation of TEM-1 β-lactamase to two novel antibiotics.
Article in Evolutionary applications, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
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- Mistranslation can promote the exploration of alternative evolutionary trajectories in enzyme evolution.Journal of evolutionary biology · 2021Article
- Allogenous Selection of Mutational Collateral Resistance: Old Drugs Select for New Resistance Within Antibiotic Families.Frontiers in microbiology · 2021Review
- Evolving generalists in switching rugged landscapes.PLoS computational biology · 2019Article
- High-Order Epistasis in Catalytic Power of Dihydrofolate Reductase Gives Rise to a Rugged Fitness Landscape in the Presence of Trimethoprim Selection.Molecular biology and evolution · 2019Article
- Experimental Design, Population Dynamics, and Diversity in Microbial Experimental Evolution.Microbiology and molecular biology reviews : MMBR · 2018Review
- Network Analysis of Protein Adaptation: Modeling the Functional Impact of Multiple Mutations.Molecular biology and evolution · 2018Article
- Multicopy plasmids allow bacteria to escape from fitness trade-offs during evolutionary innovation.Nature ecology & evolution · 2018Article
- Slow and temperature-mediated pathogen adaptation to a nonspecific fungicide in agricultural ecosystem.Evolutionary applications · 2018Article
- Adaptive benefits from small mutation supplies in an antibiotic resistance enzyme.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Time-programmable drug dosing allows the manipulation, suppression and reversal of antibiotic drug resistance in vitro.Nature communications · 2017Article
- Mistranslation can enhance fitness through purging of deleterious mutations.Nature communications · 2017Article
- Effect of Host Species on Topography of the Fitness Landscape for a Plant RNA Virus.Journal of virology · 2016Article
- How mutational epistasis impairs predictability in protein evolution and design.Protein science : a publication of the Protein Society · 2016Article
- Causes of molecular convergence and parallelism in protein evolution.Nature reviews. Genetics · 2016Review
- Potential of Tetracycline Resistance Proteins To Evolve Tigecycline Resistance.Antimicrobial agents and chemotherapy · 2016Article
- Environmental changes bridge evolutionary valleys.Science advances · 2016Article
- Temporal variation in antibiotic environments slows down resistance evolution in pathogenic Pseudomonas aeruginosa.Evolutionary applications · 2015Article
- Breaking evolutionary constraint with a tradeoff ratchet.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pleiotropy is a key feature of the genotype-phenotype map, and its form and extent have many evolutionary implications, including for the dynamics of adaptation and the evolution of specialization. Similarly, pleiotropic effects of antibiotic resistance mutations may affect the evolution of antibiotic resistance in the simultaneous or fluctuating presence of different antibiotics. Here, we study the role of pleiotropy during the in vitro adaptation of the enzyme TEM-1 β-lactamase to two novel antibiotics, cefotaxime (CTX) and ceftazidime (CAZ). We subject replicate lines for four rounds of evolution to selection with CTX and CAZ alone, and in their combined and fluctuating presence. Evolved alleles show positive correlated responses when selecting with single antibiotics. Nevertheless, pleiotropic constraints are apparent from the effects of single mutations and from selected alleles showing smaller correlated than direct responses and smaller responses after simultaneous and fluctuating selection with both than with single antibiotics. We speculate that these constraints result from structural changes in the oxyanion pocket surrounding the active site, where accommodation of CTX and the larger CAZ is balanced against their positioning with respect to the active site. Our findings suggest limited benefits from the combined or fluctuating application of these related cephalosporins for containing antibiotic resistance.
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