Apidaecin is a proline-rich antimicrobial peptide produced by honeybees. It reaches the cytoplasm of Gram-negative bacteria via the SbmA transporter located in the inner membrane. In the cytoplasm, Apidaecin displays a unique mechanism of action: it inhibits translation termination by binding in the nascent peptide exit tunnel after peptidyl-tRNA hydrolysis and by trapping release factors on the ribosome. Structural studies show that the C-terminus of Apidaecin interacts with the P-site t-RNA and the A-site-bound release factor, while the N-terminus stretches along the length of the exit tunnel. Informed by structural and biochemical data, we have synthesized and tested synthetic Apidaecin variants in an effort to improve antimicrobial activity. We have incorporated unnatural amino acids, backbone modifications, and constraints into the Apidaecin sequence. We will present sequence modifications that enhance or diminish Apidaecin activity. These data provide compelling new research avenues for a novel antibiotic mechanism.

Optimization of the proline-rich antimicrobial peptide apidaecin

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