Clinically relevant mutations in core metabolic genes confer antibiotic resistance

Science. 2021 Feb 19;371(6531):eaba0862. doi: 10.1126/science.aba0862.


Although metabolism plays an active role in antibiotic lethality, antibiotic resistance is generally associated with drug target modification, enzymatic inactivation, and/or transport rather than metabolic processes. Evolution experiments of Escherichia coli rely on growth-dependent selection, which may provide a limited view of the antibiotic resistance landscape. We sequenced and analyzed E. coli adapted to representative antibiotics at increasingly heightened metabolic states. This revealed various underappreciated noncanonical genes, such as those related to central carbon and energy metabolism, which are implicated in antibiotic resistance. These metabolic alterations lead to lower basal respiration, which prevents antibiotic-mediated induction of tricarboxylic acid cycle activity, thus avoiding metabolic toxicity and minimizing drug lethality. Several of the identified metabolism-specific mutations are overrepresented in the genomes of >3500 clinical E. coli pathogens, indicating clinical relevance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptation, Physiological
  • Anti-Bacterial Agents / pharmacology*
  • Carbenicillin / pharmacology
  • Ciprofloxacin / pharmacology
  • Citric Acid Cycle / genetics
  • Directed Molecular Evolution
  • Drug Resistance, Bacterial / genetics*
  • Energy Metabolism / genetics
  • Escherichia coli / drug effects*
  • Escherichia coli / genetics*
  • Escherichia coli / growth & development
  • Escherichia coli / metabolism
  • Escherichia coli Infections / microbiology
  • Escherichia coli Proteins / genetics
  • Gene Knockdown Techniques
  • Genes, Bacterial*
  • Genome, Bacterial
  • Ketoglutarate Dehydrogenase Complex / genetics
  • Microbial Sensitivity Tests
  • Mutation*
  • Sequence Analysis, DNA
  • Streptomycin / pharmacology


  • Anti-Bacterial Agents
  • Escherichia coli Proteins
  • Ciprofloxacin
  • Ketoglutarate Dehydrogenase Complex
  • Carbenicillin
  • Streptomycin