Multidrug-resistant bacteria have become a serious human health problem. Consequently, antibiotic research must not only search out novel cytotoxic molecules, but also must find new methods to speed up the search process. mRNA peptide display is currently the most powerful! method to sample trillions of distinct molecules for binding activity, and therefore appeares as a promising tool for drug discovery. Although this method relies on ribosomal peptide synthesis, it may not be restricted to naturally incorporated alpha-amino acids. A variety of ?-amino acid surrogates can be included to generate peptide-based drugs that avoid the usual fates of peptides in a biological context such as proteolysis or immunogenicity. Using building blocks with electrophilic side chains could render tight binding peptides into specific irreversible inhibitors, thus increasing their bioactivity. The herein proposed research aims at the developement of a specific irreversible inhibitor for an extracellular transpeptidase (SrtA) from Staphylococcus aureus. Such a specific alkylating agent may find applications as a lead compound for new generation antibiotics but also as a tool for proteomic studies (activity-based protein profiling).
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