An antimicrobial peptide that inhibits translation by trapping release factors on the ribosome

Many antibiotics stop bacterial growth by inhibiting different steps of protein synthesis. However, no specific inhibitors of translation termination are known. Proline-rich antimicrobial peptides, a component of the antibacterial defense system of multicellular organisms, interfere with bacterial growth by inhibiting translation. Here we show that Api137, a derivative of the insect-produced antimicrobial peptide apidaecin, arrests terminating ribosomes using a unique mechanism of action. Api137 binds to the Escherichia coli ribosome and traps release factors 1 or 2 subsequent to release of the nascent polypeptide chain. A high-resolution cryo-EM structure of the ribosome complexed with release factor 1 and Api137 reveals the molecular interactions that lead to release factor trapping. Api137-mediated depletion of the cellular pool of free release factors causes the majority of ribosomes to stall at stop codons prior to polypeptide release, thereby resulting in a global shutdown of translation termination.