S29: Nucleoside and Peptide Antibiotics Inhibiting Bacterial Translocase I: Discovery and Chemoenzymatic Structural Modification

The utility of clinically used antibiotics is rapidly declining due to the emergence of resistance, and trends suggest that the supply of new antibiotics is not keeping up with the demand.  Natural products have historically been the predominant source of antibiotics, yet it is not clear what role natural products will have in the future of antibiotic drug discovery. We will present our efforts toward identifying and characterizing novel antibiotics derived from microorganisms, particularly natural product scaffolds that can be considered new molecular entities or inhibit previously unexploited targets. Specifically, we will discuss the discovery of various nucleoside and peptide antibiotics that inhibit the enzyme bacterial translocase I, and how the biosynthetic enzymes for these compounds can be exploited to enrich the chemistry not normally observed in the natural product as a means to explore the structure-activity relationship and to fine-tune the pharmacological properties and antimicrobial activity.