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Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection

Patel, V and Matange, N (2021) Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection. In: eLife, 10 .

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Official URL: https://doi.org/10.7554/eLife.70931


Gene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that the early evolutionary response of Escherichia coli to the antibiotic trimethoprim involves derepression of PhoPQ signaling, an Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that dere-pression of PhoPQ confers trimethoprim-tolerance to E. coli by hitherto unrecognized transcriptional upregulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in mgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing, and mutation re-construction, we show that populations of E. coli challenged with trimethoprim are faced with the evolutionary ‘choice’ of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ derepression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are deter-mined by the strength of antibiotic selection, such that high pressures favor resistance, while low pressures favor cost compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link. ‍© Patel and Matange.

Item Type: Journal Article
Publication: eLife
Publisher: eLife Sciences Publications Ltd
Additional Information: The copyright for this article belongs to the Authors.
Keywords: ampicillin; antibiotic agent; chloramphenicol; congo red; dihydrofolate reductase; genomic DNA; kanamycin; magnesium ion; MgrB; polyhistidine tag; sigma factor RpoS; trimethoprim; unclassified drug; antiinfective agent; Escherichia coli protein; trimethoprim, amino acid sequence; antibiotic resistance; antibiotic sensitivity; Article; bacterial gene; bacterial strain; bacterium colony; bacterium culture; cell growth assay; Citrobacter freundii; deoA; DNA extraction; DNA sequencing; dnaA; drug exposure; Escherichia coli; evolutionary adaptation; folA; gel mobility shift assay; gene; gene expression; gene expression regulation; gene mutation; gene regulatory network; genome analysis; hexR; high throughput sequencing; immunoblotting; laboratory test; mcrC; mgrB; minimum inhibitory concentration; mutation; nonhuman; PhoP; plasmid; polymerase chain reaction; protein purification; Salmonella; Sanger sequencing; signal transduction; staining; trimethoprim resistance; upregulation; whole genome sequencing; yagF; yagH; ybcM; ycaQ; drug effect; gene regulatory network; genetics; molecular evolution, Anti-Bacterial Agents; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Proteins; Evolution, Molecular; Gene Regulatory Networks; Genes, Bacterial; Mutation; Tetrahydrofolate Dehydrogenase; Trimethoprim
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 05 Jun 2023 10:53
Last Modified: 05 Jun 2023 10:53
URI: https://eprints.iisc.ac.in/id/eprint/81776

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