The Antibiotic Dosage of Fastest Resistance Evolution: Gene Amplifications Underpinning the Inverted-U
| Autor: | Carlos Reding, Robert E. Beardmore, Gunther Jansen, Phillip Rosenstiel, Hinrich Schulenburg, Pablo Catalán, Tobias Bergmiller, Ivana Gudelj, Emily Wood |
|---|---|
| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España) |
| Rok vydání: | 2021 |
| Předmět: |
antibiotic resistance
DNA Copy Number Variations prophage medicine.drug_class Antibiotic resistance Matemáticas Antibiotics Microbial Sensitivity Tests Integron AcademicSubjects/SCI01180 Antiporters microbial evolution 03 medical and health sciences Minimum inhibitory concentration Genetics medicine Escherichia coli Copy-number variation Insertion sequence Molecular Biology Gene Ecology Evolution Behavior and Systematics Selection for resistance Biología y Biomedicina Discoveries 030304 developmental biology 0303 health sciences biology 030306 microbiology Microbial evolution Escherichia coli Proteins efflux pump AcrAB-TolC Gene Amplification AcademicSubjects/SCI01130 selection for resistance Efflux pump acrAB-TolC Anti-Bacterial Agents Genomic amplification genomic amplification biology.protein Prophage Efflux |
| Zdroj: | Molecular Biology and Evolution e-Archivo. Repositorio Institucional de la Universidad Carlos III de Madrid instname |
| ISSN: | 1537-1719 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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