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Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids
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The proline-rich antimicrobial peptide Api137 disrupts large ribosomal subunit assembly and induces misfolding

Simon Malte Lauer1,2, Jakob Gasse3,4, Andor Krizsan3,4

  • 1Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany.

Nature Communications
|January 10, 2025
PubMed

Insights

The antimicrobial peptide Api137 disrupts bacterial 50S ribosomal subunit assembly, creating non-functional precursors. This novel mechanism contributes to its potent bactericidal activity, offering new therapeutic avenues.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Structural Biology

Background:

  • The antimicrobial peptide Api137 inhibits bacterial protein synthesis by targeting the ribosome and release factors.
  • Understanding the full spectrum of Api137's action is crucial for developing new antibacterial strategies.

Purpose of the Study:

  • To investigate the impact of Api137 on bacterial ribosome assembly.
  • To elucidate the structural basis of Api137-induced ribosome assembly defects.

Main Methods:

  • Utilized an Escherichia coli reporter strain with fluorescently tagged ribosomal proteins.
  • Employed sucrose gradient centrifugation to analyze ribosome assembly intermediates.
  • Determined high-resolution structures of precursor particles using cryogenic electron microscopy.

Main Results:

  • Api137 treatment led to an accumulation of partially assembled 50S ribosomal subunit precursors (pre-50S).
  • Cryo-EM structures revealed that these pre-50S particles were missing key ribosomal proteins and exhibited misfolded rRNA helices.
  • These defects suggest that Api137 hinders the maturation of functional 50S subunits.

Conclusions:

  • Api137 possesses a second mechanism of action beyond inhibiting protein synthesis: it disrupts 50S ribosomal subunit assembly.
  • This disruption leads to the formation of non-functional ribosomal precursors, contributing to the peptide's bactericidal effect.
  • Api137 represents a promising lead compound for developing novel antibiotics targeting bacterial ribosome biogenesis.

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