Structure of the mammalian antimicrobial peptide Bac7(1-16) bound within the exit tunnel of a bacterial ribosome

Nucleic Acids Res. 2016 Mar 18;44(5):2429-38. doi: 10.1093/nar/gkv1545. Epub 2016 Jan 20.


Proline-rich antimicrobial peptides (PrAMPs) produced as part of the innate immune response of animals, insects and plants represent a vast, untapped resource for the treatment of multidrug-resistant bacterial infections. PrAMPs such as oncocin or bactenecin-7 (Bac7) interact with the bacterial ribosome to inhibit translation, but their supposed specificity as inhibitors of bacterial rather than mammalian protein synthesis remains unclear, despite being key to developing drugs with low toxicity. Here, we present crystal structures of the Thermus thermophilus 70S ribosome in complex with the first 16 residues of mammalian Bac7, as well as the insect-derived PrAMPs metalnikowin I and pyrrhocoricin. The structures reveal that the mammalian Bac7 interacts with a similar region of the ribosome as insect-derived PrAMPs. Consistently, Bac7 and the oncocin derivative Onc112 compete effectively with antibiotics, such as erythromycin, which target the ribosomal exit tunnel. Moreover, we demonstrate that Bac7 allows initiation complex formation but prevents entry into the elongation phase of translation, and show that it inhibits translation on both mammalian and bacterial ribosomes, explaining why this peptide needs to be stored as an inactive pro-peptide. These findings highlight the need to consider the specificity of PrAMP derivatives for the bacterial ribosome in future drug development efforts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / pharmacology
  • Binding Sites
  • Binding, Competitive
  • Cattle
  • Crystallography, X-Ray
  • Erythromycin / chemistry
  • Erythromycin / pharmacology
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Heteroptera / chemistry
  • Insect Proteins / chemistry
  • Insect Proteins / pharmacology
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology
  • Protein Binding
  • Protein Biosynthesis / drug effects*
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism
  • RNA, Transfer / chemistry
  • RNA, Transfer / metabolism
  • Ribosomes / chemistry
  • Ribosomes / drug effects*
  • Ribosomes / metabolism
  • Species Specificity
  • Thermus thermophilus / chemistry


  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Insect Proteins
  • Peptides, Cyclic
  • RNA, Messenger
  • bactenecin
  • pyrrhocoricin protein, Pyrrhocoris apterus
  • Erythromycin
  • RNA, Transfer