ArticleProceedings of the National Academy of Sciences of the United States of America2012
Small changes in enzyme function can lead to surprisingly large fitness effects during adaptive evolution of antibiotic resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
33 citing papers in PubMed.
- Evolution, Mechanisms, and Therapeutic Implications of Mobile Tetracycline Destructases.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- Experimental Evolution of Yeast Reveals Trade-offs Between Early and Late Stationary Phase.bioRxiv : the preprint server for biology · 2026Article
- The genetic basis of the leafy seadragon's unique camouflage morphology and avenues for its efficient conservation derived from habitat modeling.Science China. Life sciences · 2023Article
- Structure of anhydrotetracycline-bound Tet(X6) reveals the mechanism for inhibition of type 1 tetracycline destructases.Communications biology · 2023Article
- Excreted Antibiotics May Be Key to Emergence of Increasingly Efficient Antibiotic Resistance in Food Animal Production.Applied and environmental microbiology · 2022Article
- Functional and phylogenetic analysis of TetX variants to design a new classification system.Communications biology · 2022Article
- Phylogenetic convergence of phase separation and mitotic function in the disordered protein BuGZ.Protein science : a publication of the Protein Society · 2022Article
- Association Analysis between Genetic Variants ofBiology · 2022Article
- Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites.Cell chemical biology · 2022Article
- Structural and mechanistic basis of the high catalytic activity of monooxygenase Tet(X4) on tigecycline.BMC biology · 2021Article
- Antibiotic-Resistant Genes and Bacteria as Evolving Contaminants of Emerging Concerns (e-CEC): Is It Time to Include Evolution in Risk Assessment?Antibiotics (Basel, Switzerland) · 2021Article
- Experimental Design, Population Dynamics, and Diversity in Microbial Experimental Evolution.Microbiology and molecular biology reviews : MMBR · 2018Review
- Selecting among three basic fitness landscape models: Additive, multiplicative and stickbreaking.Theoretical population biology · 2018Article
- Experimental Determination and Prediction of the Fitness Effects of Random Point Mutations in the Biosynthetic Enzyme HisA.Molecular biology and evolution · 2018Article
- Using experimental evolution to identify druggable targets that could inhibit the evolution of antimicrobial resistance.The Journal of antibiotics · 2018Article
- Polymorphism of antibiotic-inactivating enzyme driven by ecology expands the environmental resistome.The ISME journal · 2018Article
- Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer.Molecular systems biology · 2017Article
- Article
- Ribosome Mediated Quinary Interactions Modulate In-Cell Protein Activities.Biochemistry · 2017Article
- Enzyme Efficiency but Not Thermostability Drives Cefotaxime Resistance Evolution in TEM-1 β-Lactamase.Molecular biology and evolution · 2017Article
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6 authors.
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Abstract
In principle, evolutionary outcomes could be largely predicted if all of the relevant physicochemical variants of a particular protein function under selection were known and integrated into an appropriate physiological model. We have tested this principle by generating a family of variants of the tetracycline resistance protein TetX2 and identified the physicochemical properties most correlated with organismal fitness. Surprisingly, small changes in the K(m(MCN)), less than twofold, were sufficient to produce highly successful adaptive mutants over clinically relevant drug concentrations. We then built a quantitative model directly relating the in vitro physicochemical properties of the mutant enzymes to the growth rates of bacteria carrying a single chromosomal copy of the tet(X2) variants over a wide range of minocycline (MCN) concentrations. Importantly, this model allows the prediction of enzymatic properties directly from cellular growth rates as well as the physicochemical-fitness landscape of TetX2. Using experimental evolution and deep sequencing to monitor the allelic frequencies of the seven most biochemically efficient TetX2 mutants in 10 independently evolving populations, we showed that the model correctly predicted the success of the two most beneficial variants tet(X2)(T280A) and tet(X2)(N371I). The structure of the most efficient variant, TetX2(T280A), in complex with MCN at 2.7 Å resolution suggests an indirect effect on enzyme kinetics. Taken together, these findings support an important role for readily accessible small steps in protein evolution that can, in turn, greatly increase the fitness of an organism during natural selection.
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