title: Metabolic constraints on the evolution of antibiotic resistance.
abstract: 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 evolvedEscherichia coligrowing 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.
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland zampieri@imsb.biol.ethz.ch sauer@imsb.biol.ethz.ch.
authors.forename: Mattia
authors.initials: M
authors.lastname: Zampieri
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.|Institute of Biogeochemistry and Pollutant Dynamics (IBP), ETH Zürich, Zürich, Switzerland.
authors.forename: Tim
authors.initials: T
authors.lastname: Enke
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Victor
authors.initials: V
authors.lastname: Chubukov
authors.affiliation: Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Vito
authors.initials: V
authors.lastname: Ricci
authors.affiliation: Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Piddock
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland zampieri@imsb.biol.ethz.ch sauer@imsb.biol.ethz.ch.
authors.forename: Uwe
authors.identifier: 0000-0002-5923-0770
authors.initials: U
authors.lastname: Sauer
mesh_terms: D000667:Ampicillin / Q000494:pharmacology*; D005075:Biological Evolution; D004269:DNA, Bacterial / Q000032:analysis; D004352:Drug Resistance, Microbial; D004734:Energy Metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005943:Gluconeogenesis; D006019:Glycolysis; D055432:Metabolomics / Q000379:methods*; D017422:Sequence Analysis, DNA
chemical_list: D004269:DNA, Bacterial; D000667:Ampicillin
keywords: antibiotic resistance; constraint‐based modeling; efflux pump; evolution; metabolism