title: Compensation of the metabolic costs of antibiotic resistance by physiological adaptation in Escherichia coli.
abstract: Antibiotic resistance is often associated with metabolic costs. To investigate the metabolic consequences of antibiotic resistance, the genomic and transcriptomic profiles of an amoxicillin-resistant Escherichia coli strain and the wild type it was derived from were compared. A total of 125 amino acid substitutions and 7 mutations that were located <1,000 bp upstream of differentially expressed genes were found in resistant cells. However, broad induction and suppression of genes were observed when comparing the expression profiles of resistant and wild-type cells. Expression of genes involved in cell wall maintenance, DNA metabolic processes, cellular stress response, and respiration was most affected in resistant cells regardless of the absence or presence of amoxicillin. The SOS response was downregulated in resistant cells. The physiological effect of the acquisition of amoxicillin resistance in cells grown in chemostat cultures consisted of an initial increase in glucose consumption that was followed by an adaptation process. Furthermore, no difference in maintenance energy was observed between resistant and sensitive cells. In accordance with the transcriptomic profile, exposure of resistant cells to amoxicillin resulted in reduced salt and pH tolerance. Taken together, the results demonstrate that the acquisition of antibiotic resistance in E. coli is accompanied by specifically reorganized metabolic networks in order to circumvent metabolic costs. The overall effect of the acquisition of resistance consists not so much of an extra energy requirement, but more a reduced ecological range.
authors.affiliation: University of Amsterdam, Laboratory for Molecular Biology and Microbial Food Safety, Swammerdam Institute of Life Sciences, Amsterdam, The Netherlands.
authors.forename: Nadine
authors.initials: N
authors.lastname: Händel
authors.forename: J Merijn
authors.initials: JM
authors.lastname: Schuurmans
authors.forename: Stanley
authors.initials: S
authors.lastname: Brul
authors.forename: Benno H
authors.initials: BH
authors.lastname: ter Kuile
mesh_terms: D000222:Adaptation, Physiological; D019943:Amino Acid Substitution; D000658:Amoxicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003470:Culture Media / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D000900:Anti-Bacterial Agents; D003470:Culture Media; D017382:Reactive Oxygen Species; D012965:Sodium Chloride; D000658:Amoxicillin