The Mechanism of Inhibition of Protein Synthesis by the Proline- Rich Peptide Oncocin

Antibiotic-resistant bacteria are a global health issue, which necessitate the development of new effective therapeutics. Proline-rich antimicrobial peptides (PrAMPs), which include oncocins, are an extensively studied class of AMPs counteracting bacterial infection at submicromolar concentrations. Oncocins enter and kill bacteria by inhibiting certain targets, and not through membrane lysis. Although recently reported to bind DnaK and the bacterial ribosome, their mode of inhibition remains elusive. Here we report the crystal structure of the oncocin derivative, onc112, bound to the Thermus thermophilus 70S ribosome. Strikingly, this 19-residue-long proline-rich peptide manifests the features of several known classes of ribosome inhibitors by simultaneously blocking the peptidyl transferase center and the peptide exit tunnel of the ribosome. This high-resolution structure thus reveals the mechanism by which oncocins inhibit protein synthesis, providing an opportunity for structure-based design of new generation therapeutics. Throughout the course of evolution, the innate immune system in plants and animals has developed efficient ways to counter infections. One of the defense lines is through the synthesis of antimicrobial peptides that kill bacterial and fungal pathogens 1–3. These AMP