Fusidic acid-resistant EF-G perturbs the accumulation of ppGpp

Mirjana Macvanin, Urban Johanson, Måns Ehrenberg, Diarmaid Hughes

Research output: Contribution to journalArticlepeer-review

35 Citations (SciVal)

Abstract

Reductions in growth rate caused by fusidic acid-resistant EF-G mutants in Salmonella typhimurium correlate strongly with increased mean cell size. This is unusual because growth rate and cell size normally correlate positively. The global transcription regulator molecule ppGpp has a role in co-ordinating growth rate and division, and its basal level normally correlates inversely with cell size at division. We show that fusidic acid-resistant EF-G mutants have perturbed ppGpp basal levels during steady-state growth and perturbed induced levels during starvation. One mutation, fusA1, associated with the slowest growth rate and largest cell size, causes a reduction in the basal level of ppGpp to one-third of that found in the wild-type strain. Other fusA mutants with intermediate or wild-type growth rates and cell sizes have either normal or increased basal levels of ppGpp. There is an inverse relationship between the basal level of ppGpp in vivo and the degree to which translation dependent on mutant EF-G is inhibited by ppGpp in vitro. This enhanced interaction between mutant EF-G and ppGpp correlates with an increased KM for GTP. Our results suggest that mutant EF-G modulates the production of ppGpp by the RelA (PSI) pathway. In conclusion, fusidic acid-resistant EF-G mutations alter the level of ppGpp and break the normal relationship between growth rate and cell size at division. It would not be surprising if other phenotypes associated with these mutants, such as loss of virulence, were also related to perturbations in ppGpp levels effected through altered transcription patterns.
Original languageEnglish
Pages (from-to)98-107
JournalMolecular Microbiology
Volume37
Issue number1
DOIs
Publication statusPublished - 2000

Subject classification (UKÄ)

  • Biological Sciences

Keywords

  • development/metabolism
  • Guanosine Tetraphosphate/*metabolism
  • Fusidic Acid/*pharmacology
  • Microbial
  • Anti-Bacterial Agents/*pharmacology
  • Drug Resistance
  • Mutation
  • Peptide Elongation Factor G/drug effects/genetics/*metabolism
  • Salmonella typhimurium/*drug effects/genetics/growth &
  • Protein Biosynthesis

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