Abstract 1459 Structure-Based Design and Development of Phosphine Oxides as a Novel Chemotype for Antibiotics that Dysregulate Bacterial ClpP Proteases

Due to the rise of antibiotic resistance in bacterial pathogens, there remains a large unmet need for novel therapeutic antibiotics to treat infections.Novel molecules with diverse structures that target different cellular machinery are of high importance as the majority of clinical antibiotics rely on inhibiting the same targets and make use of similar chemical scaffolds, which are susceptible to resistance.Promising research has shown that the bacterial ClpP protease, involved in protein homeostasis, is a viable target for antibiotic drug development.A previous chemical screen from our group has identified novel scaffolds that dysregulate the protease and were termed Activators of Self-Compartmentalized Proteases (ACPs) due to their ability to cause the nonspecific degradation of essential cellular housekeeping proteins, ultimately resulting in cell death.Co-crystal structure data of compound-ClpP complexes suggested that ACPs adopt two configurations in the binding site.A new class of ACP compounds has been developed that leverages a phosphine oxide moiety connecting the two aryl groups to adopt both configurations in the binding pocket.Using this strategy, novel derivatives were synthesized in the initial medicinal chemistry panel, expanding the chemical space of the analogs.The analogs were then screened for activity against ClpP, and hits were prioritized in subsequent biological assays.Lastly, activity results and co-crystal structures validate the structure-based approach to drug discovery as efficacy was improved and the binding conformation