Synthesis and Evaluation of Prp-Specific Probes and Prodrugs

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Project Summary/Abstract New antibiotic targets are needed to combat antibiotic-resistant bacteria. A new potential drug target is a phage-related ribosomal protease (Prp), which is used by a variety of Firmicutes pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. These pathogens use Prp for ribosomal maturation. Prp is a cysteine protease that cleaves an N-terminal extension of the ribosomal protein L27, and in the case of S. aureus, Prp is essential for survival. Since most bacteria do not contain this N- terminal extension on L27 and do not encode Prp, targeting it should lead to less killing of commensal bacteria that are important for human health. Different pathogens that use Prps have distinctive L27 cleavable sequences. In this proposal, we will study the cross-selectivity and kinetics of L27 sequence cleavage by different Prps. We will identify the minimal L27 N-terminal sequence required for recognition and processing by Prp, and the L27 N-terminal sequence length required for cross-species Prp selectivity. These lessons will be applied to the synthesis of Prp activated prodrugs of ciprofloxacin and eperezolid. These prodrugs will be tested for activity and selectivity against the Prp-containing pathogens S. aureus, S. pneumoniae, and C. difficile, as well as the Prp-containing commensal bacteria Lactobacillus rhamnosus. These studies will greatly increase our knowledge of the selectivity and reactivity of Prps, and allow for the targeted killing of bacteria that use them.