ArticleProceedings of the National Academy of Sciences of the United States of America2016
Biophysical principles predict fitness landscapes of drug resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 96 papers.
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Who cites it
96 citing papers in PubMed, 178 citations in OpenAlex.
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- Metabolite correlation networks reveal complex phenotypes of adaptation-driving mutations.Nature communications · 2026Article
- Deconstructing empirical fitness seascapes across scales of granularity.G3 (Bethesda, Md.) · 2026Article
- Polymorphisms in a bacterial signalling pathway alter evolutionary routes of antibiotic resistance in Escherichia coli.PLoS biology · 2026Article
- Enzyme kinetics shapes the growth response of metabolic networks.PLoS computational biology · 2026Article
- Chaperonin recognition of protein dynamics drives drug resistance.bioRxiv : the preprint server for biology · 2026Article
- Co-targeting Metabolic Neighbours Constraints Bacterial Adaptive Evolution.bioRxiv : the preprint server for biology · 2026Article
- Deconstructing empirical fitness seascapes across scales of granularity.bioRxiv : the preprint server for biology · 2026Article
- Dynamic signature of activity-stability tradeoff in lactamase evolution.Nature communications · 2026Article
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- Protein Quality Control is a Master Modulator of Molecular Evolution in Bacteria.Genome biology and evolution · 2025Review
- Exploring Novel Antibiotics by Targeting the GroEL/GroES Chaperonin System.ACS pharmacology & translational science · 2025Review
- Bioengineering hybrid artificial life.Frontiers in bioinformatics · 2025Review
- Concepts and Methods for Predicting Viral Evolution.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Concepts and methods for predicting viral evolution.bioRxiv : the preprint server for biology · 2024Article
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- Evolution of evolvability in rapidly adapting populations.Nature ecology & evolution · 2024Article
- Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs.eLife · 2024Article
36 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.
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