Many new antimicrobials are analogs of existing drugs, sharing the same targets and mechanisms of action. New antibiotic targets are critically needed to combat the growing threat of antimicrobial-resistant bacteria. Phage-related ribosomal proteases (Prps) are a recently structurally characterized antibiotic target found in pathogens such as Staphylococcus aureus, Clostridioides difficile, and Streptococcus pneumoniae. These bacteria encode an N-terminal extension on their ribosomal protein L27 that is not present in other bacteria. The cleavage of this N-terminal extension from L27 by Prp is necessary to create a functional ribosome. Thus, Prp inhibition may serve as an alternative to direct binding and inhibition of the ribosome. This bioinformatic and structural analysis covers the discovery, function, and structural characteristics of known Prps. This information will be helpful in future endeavors to design selective therapeutics targeting the Prps of important pathogens.
Keywords: X-ray crystal structure; antimicrobials; bioinformatics; new targets; phage-related ribosomal protease.