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

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dc.contributor.author PATEL, VISHWA en_US
dc.contributor.author MATANGE, NISHAD en_US
dc.date.accessioned 2021-10-18T10:30:52Z
dc.date.available 2021-10-18T10:30:52Z
dc.date.issued 2021-09 en_US
dc.identifier.citation eLife, 10. en_US
dc.identifier.issn 2050-084X en_US
dc.identifier.uri https://doi.org/10.7554/eLife.70931 en_US
dc.identifier.uri http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/6325
dc.description.abstract 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 derepression 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 determined 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. en_US
dc.language.iso en en_US
dc.publisher eLife Sciences Publications Ltd. en_US
dc.subject Experimental evolution en_US
dc.subject Gene regulatory networks en_US
dc.subject Anti-microbial resistance en_US
dc.subject MgrB en_US
dc.subject Compensatory evolution en_US
dc.subject Trimethoprim en_US
dc.subject Ecoli en_US
dc.subject 2021-OCT-WEEK1 en_US
dc.subject TOC-OCT-2021 en_US
dc.subject 2021 en_US
dc.title Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection en_US
dc.type Article en_US
dc.contributor.department Dept. of Biology en_US
dc.identifier.sourcetitle eLife en_US
dc.publication.originofpublisher Foreign en_US


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