Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size

Cell Rep. 2016 Aug 16;16(7):1789-99. doi: 10.1016/j.celrep.2016.07.018. Epub 2016 Aug 4.


Macrolide antibiotic binding to the ribosome inhibits catalysis of peptide bond formation between specific donor and acceptor substrates. Why particular reactions are problematic for the macrolide-bound ribosome remains unclear. Using comprehensive mutational analysis and biochemical experiments with synthetic substrate analogs, we find that the positive charge of these specific residues and the length of their side chains underlie inefficient peptide bond formation in the macrolide-bound ribosome. Even in the absence of antibiotic, peptide bond formation between these particular donors and acceptors is rather inefficient, suggesting that macrolides magnify a problem present for intrinsically difficult substrates. Our findings emphasize the existence of functional interactions between the nascent protein and the catalytic site of the ribosomal peptidyl transferase center.

MeSH terms

  • Amino Acid Motifs
  • Base Sequence
  • Binding Sites
  • Escherichia coli / drug effects*
  • Escherichia coli / genetics
  • Escherichia coli / growth & development
  • Escherichia coli / metabolism
  • Macrolides / chemistry
  • Macrolides / pharmacology*
  • Peptidyl Transferases / genetics
  • Peptidyl Transferases / metabolism
  • Protein Biosynthesis / drug effects*
  • Protein Synthesis Inhibitors / chemistry
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA, Transfer, Amino Acyl / genetics
  • RNA, Transfer, Amino Acyl / metabolism*
  • Ribosomes / drug effects*
  • Ribosomes / metabolism
  • Static Electricity
  • Substrate Specificity


  • Macrolides
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • RNA, Transfer, Amino Acyl
  • Peptidyl Transferases