The antibiotic dosage of fastest resistance evolution: Gene amplifications underpinning the inverted-U

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dc.contributor.author Reding, Carlos
dc.contributor.author Catalan Fernandez, Pablo
dc.contributor.author Jansen, Gunther
dc.contributor.author Bergmiller, Tobias
dc.contributor.author Wood, Emily
dc.contributor.author Rosenstiel, Phillip
dc.contributor.author Schulenburg, Hinrich
dc.contributor.author Gudelj, Ivana
dc.contributor.author Beardmore, Robert
dc.date.accessioned 2022-02-02T10:38:24Z
dc.date.available 2022-02-02T10:38:24Z
dc.date.issued 2021-09
dc.identifier.bibliographicCitation Reding, C., Catalán, P., Jansen, G., Bergmiller, T., Wood, E., Rosenstiel, P., Schulenburg, H., Gudelj, I. & Beardmore, R. (2021). The Antibiotic Dosage of Fastest Resistance Evolution: Gene Amplifications Underpinning the Inverted-U. Molecular Biology and Evolution, 38(9), 3847–3863.
dc.identifier.issn 0737-4038
dc.identifier.uri http://hdl.handle.net/10016/34012
dc.description.abstract To determine the dosage at which antibiotic resistance evolution is most rapid, we treated Escherichia coli in vitro, deploying the antibiotic erythromycin at dosages ranging from zero to high. Adaptation was fastest just below erythromycin’s minimal inhibitory concentration (MIC) and genotype-phenotype correlations determined from whole genome sequencing revealed the molecular basis: simultaneous selection for copy number variation in three resistance mechanisms which exhibited an “inverted-U” pattern of dose-dependence, as did several insertion sequences and an integron. Many genes did not conform to this pattern, however, reflecting changes in selection as dose increased: putative media adaptation polymorphisms at zero antibiotic dosage gave way to drug target (ribosomal RNA operon) amplification at mid dosages whereas prophage-mediated drug efflux amplifications dominated at the highest dosages. All treatments exhibited E. coli increases in the copy number of efflux operons acrAB and emrE at rates that correlated with increases in population density. For strains where the inverted-U was no longer observed following the genetic manipulation of acrAB, it could be recovered by prolonging the antibiotic treatment at subMIC dosages.
dc.description.sponsorship P.C. was supported by a Ramón Areces Postdoctoral Fellowship and by Ministerio de Ciencia, Innovación y Universidades/FEDER (Spain/UE) through Grant numbers PGC2018-098186-B-I00 (BASIC) and PID2019-109320GB-I00. RB and CR were supported by UKRI(EPSRC) grants EP/N033671/1 and EP/I00503X/1, EW was supported by a UKRI(BBSRC) DTP block grant (SWBio) awarded to Exeter University.
dc.format.extent 17
dc.language.iso eng
dc.publisher Oxford University Press
dc.rights © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
dc.rights Atribución 3.0 España
dc.rights.uri http://creativecommons.org/licenses/by/3.0/es/
dc.subject.other Antibiotic resistance
dc.subject.other Efflux pump acrAB-TolC
dc.subject.other Genomic amplification
dc.subject.other Microbial evolution
dc.subject.other Prophage
dc.subject.other Selection for resistance
dc.title The antibiotic dosage of fastest resistance evolution: Gene amplifications underpinning the inverted-U
dc.type article
dc.subject.eciencia Biología y Biomedicina
dc.subject.eciencia Matemáticas
dc.identifier.doi https://doi.org/10.1093/molbev/msab025
dc.rights.accessRights openAccess
dc.relation.projectID Gobierno de España. PGC2018-098186-B-I00
dc.relation.projectID Gobierno de España. PID2019-109320GB-I00
dc.type.version publishedVersion
dc.identifier.publicationfirstpage 3847
dc.identifier.publicationissue 9
dc.identifier.publicationlastpage 3863
dc.identifier.publicationtitle Molecular Biology and Evolution
dc.identifier.publicationvolume 38
dc.identifier.uxxi AR/0000028880
dc.contributor.funder Ministerio de Ciencia, Innovación y Universidades (España)
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