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dc.contributor.authorPalmer, AC
dc.contributor.authorChait, R
dc.contributor.authorKishony, R
dc.date.accessioned2019-03-15T09:22:33Z
dc.date.issued2018-08-28
dc.description.abstractBacteria regulate genes to survive antibiotic stress, but regulation can be far from perfect. When regulation is not optimal, mutations that change gene expression can contribute to antibiotic resistance. It is not systematically understood to what extent natural gene regulation is or is not optimal for distinct antibiotics, and how changes in expression of specific genes quantitatively affect antibiotic resistance. Here we discover a simple quantitative relation between fitness, gene expression, and antibiotic potency, which rationalizes our observation that a multitude of genes and even innate antibiotic defense mechanisms have expression that is critically nonoptimal under antibiotic treatment. First, we developed a pooled-strain drug-diffusion assay and screened Escherichia coli overexpression and knockout libraries, finding that resistance to a range of 31 antibiotics could result from changing expression of a large and functionally diverse set of genes, in a primarily but not exclusively drug-specific manner. Second, by synthetically controlling the expression of single-drug and multidrug resistance genes, we observed that their fitness-expression functions changed dramatically under antibiotic treatment in accordance with a log-sensitivity relation. Thus, because many genes are nonoptimally expressed under antibiotic treatment, many regulatory mutations can contribute to resistance by altering expression and by activating latent defenses.en_GB
dc.description.sponsorshipNational Institutes of Healthen_GB
dc.description.sponsorshipIsraeli Centers of Research Excellence I-CORE Programen_GB
dc.description.sponsorshipEuropean Research Councilen_GB
dc.description.sponsorshipNational Health and Medical Research Councilen_GB
dc.identifier.citationVol. 35 (11), pp. 2669 - 2684en_GB
dc.identifier.doi10.1093/molbev/msy163
dc.identifier.grantnumberR01-GM081617en_GB
dc.identifier.grantnumber152/11en_GB
dc.identifier.grantnumber281891en_GB
dc.identifier.grantnumber1072965en_GB
dc.identifier.urihttp://hdl.handle.net/10871/36476
dc.language.isoenen_GB
dc.publisherOxford University Press (OUP)en_GB
dc.rights(C) The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en_GB
dc.subjectsystems biologyen_GB
dc.subjectantibiotic resistanceen_GB
dc.subjectevolutionen_GB
dc.subjectgene expressionen_GB
dc.titleNonoptimal Gene Expression Creates Latent Potential for Antibiotic Resistanceen_GB
dc.typeArticleen_GB
dc.date.available2019-03-15T09:22:33Z
dc.identifier.issn0737-4038
dc.descriptionThis is the final version. Available from Oxford University Press (OUP) via the DOI in this record.en_GB
dc.identifier.journalMolecular Biology and Evolutionen_GB
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_GB
dcterms.dateAccepted2018-08-28
rioxxterms.versionVoRen_GB
rioxxterms.licenseref.startdate2018-08-28
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2019-03-15T09:17:27Z
refterms.versionFCDVoR
refterms.dateFOA2019-03-15T09:22:35Z
refterms.panelAen_GB


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(C) The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's licence is described as (C) The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.