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Metabolic constraints on the evolution of antibiotic resistance.
Journal article

Metabolic constraints on the evolution of antibiotic resistance.

  • Zampieri M Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland zampieri@imsb.biol.ethz.ch sauer@imsb.biol.ethz.ch.
  • Enke T Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
  • Chubukov V Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
  • Ricci V Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
  • Piddock L Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
  • Sauer U Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland zampieri@imsb.biol.ethz.ch sauer@imsb.biol.ethz.ch.
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  • 2017-03-08
Published in:
  • Molecular systems biology. - 2017
antibiotic resistance
constraint‐based modeling
efflux pump
evolution
metabolism
Ampicillin
Biological Evolution
DNA, Bacterial
Drug Resistance, Microbial
Energy Metabolism
Escherichia coli
Gene Expression Regulation, Bacterial
Gluconeogenesis
Glycolysis
Metabolomics
Sequence Analysis, DNA
English Despite our continuous improvement in understanding antibiotic resistance, the interplay between natural selection of resistance mutations and the environment remains unclear. To investigate the role of bacterial metabolism in constraining the evolution of antibiotic resistance, we evolved Escherichia coli growing on glycolytic or gluconeogenic carbon sources to the selective pressure of three different antibiotics. Profiling more than 500 intracellular and extracellular putative metabolites in 190 evolved populations revealed that carbon and energy metabolism strongly constrained the evolutionary trajectories, both in terms of speed and mode of resistance acquisition. To interpret and explore the space of metabolome changes, we developed a novel constraint-based modeling approach using the concept of shadow prices. This analysis, together with genome resequencing of resistant populations, identified condition-dependent compensatory mechanisms of antibiotic resistance, such as the shift from respiratory to fermentative metabolism of glucose upon overexpression of efflux pumps. Moreover, metabolome-based predictions revealed emerging weaknesses in resistant strains, such as the hypersensitivity to fosfomycin of ampicillin-resistant strains. Overall, resolving metabolic adaptation throughout antibiotic-driven evolutionary trajectories opens new perspectives in the fight against emerging antibiotic resistance.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/66517
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