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

authors

  • REDING, CARLOS
  • CATALAN FERNANDEZ, PABLO
  • JANSEN, GUNTHER
  • BERGMILLER, TOBIAS
  • WOOD, EMILY
  • ROSENSTIEL, PHILLIP
  • SCHULENBURG, HINRICH
  • GUDELJ, IVANA
  • BEARDMORE, ROBERT

publication date

  • September 2021

start page

  • 3847

end page

  • 3863

issue

  • 9

volume

  • 38

International Standard Serial Number (ISSN)

  • 0737-4038

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.

subjects

  • Biology and Biomedicine
  • Mathematics

keywords

  • antibiotic resistance; efflux pump acrab-tolc; genomic amplification; microbial evolution; prophage; selection for resistance