Choice of b-Lactam resistance pathway depends critically on initial antibiotic concentration

Philip Ruelens*, J.A. de Visser

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Antibiotic resistance trajectories with different final resistance may critically depend on the first mutation, due to epistatic interactions. Here, we study the effect of mutation bias and the concentration-dependent effects on fitness of two clinically important mutations in TEM-1 b-lactamase in initiating alternative trajectories to cefotaxime resistance. We show that at low cefotaxime concentrations, the R164S mutation (a mutation of arginine to serine at position 164), which confers relatively low resistance, is competitively superior to the G238S mutation, conferring higher resistance, thus highlighting a critical influence of antibiotic concentration on long-term resistance evolution.

Original languageEnglish
Article numbere00471-21
JournalAntimicrobial Agents and Chemotherapy
Issue number8
Publication statusPublished - 16 Jul 2021


  • Antibiotic resistance
  • B-lactamase
  • Epistasis
  • Protein evolution
  • TEM-1


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