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The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria

S M Swaney1, H Aoki, M C Ganoza

  • 1Infectious Diseases Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001, USA.

Antimicrobial Agents and Chemotherapy
|December 3, 1998
PubMed

Insights

Oxazolidinones, including linezolid, are novel antimicrobials effective against resistant bacteria. They inhibit bacterial protein synthesis by blocking the crucial initiation complex formation step.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Drug Discovery

Background:

  • Oxazolidinones are a novel class of antimicrobials.
  • They exhibit activity against multidrug-resistant Gram-positive bacteria like staphylococci, streptococci, and enterococci.
  • Previous research indicated oxazolidinones interfere with bacterial translation initiation.

Purpose of the Study:

  • To investigate the precise mechanism by which oxazolidinones, specifically linezolid, inhibit bacterial translation.
  • To determine the specific step in protein synthesis initiation that is affected by linezolid.

Main Methods:

  • Utilized an initiation complex assay to measure the binding of N-formylmethionyl-tRNA to ribosomes.
  • Assessed the effect of linezolid on the formation of the ternary complex involving N-formylmethionyl-tRNA, ribosomes, and mRNA.
  • Tested inhibition on both Escherichia coli and Staphylococcus aureus ribosomal subunits.

Main Results:

  • Linezolid inhibited initiation complex formation with both 30S and 70S ribosomal subunits from E. coli.
  • Linezolid also inhibited complex formation with Staphylococcus aureus 70S ribosomes.
  • Linezolid did not impede the independent binding of mRNA or N-formylmethionyl-tRNA to 30S subunits, nor the formation of the IF2-N-formylmethionyl-tRNA binary complex.

Conclusions:

  • Oxazolidinones, exemplified by linezolid, function by inhibiting the formation of the bacterial translation initiation complex.
  • This inhibition occurs at the stage of forming the N-formylmethionyl-tRNA-ribosome-mRNA ternary complex.
  • The findings clarify the molecular mechanism of action for this important class of antibiotics.

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