Development of Oxadiazolone Activity-Based Probes Targeting FphE for Specific Detection ofS. aureusInfections

Abstract

Staphylococcus aureusis a major human pathogen responsible for a wide range of systemic infections. Since its propensity to form biofilmsin vivoposes formidable challenges for both detection and treatment, tools that can be used to specifically imageS. aureusbiofilms are highly valuable for clinical management. Here we describe the development of oxadiazolone-based activity-based probes to target theS. aureus-specific serine hydrolase FphE. Because this enzyme lacks homologs in other bacteria, it is an ideal target for selective imaging ofS. aureusinfections. Using X-ray crystallography, direct cell labeling and mouse models of infection we demonstrate that oxadiazolone-based probes enable specific labeling ofS. aureusbacteria through the direct covalent modification of the FphE active site serine. These results demonstrate the utility of the oxadizolone electrophile for activity-based probes (ABPs) and validate FphE as a target for development of imaging contrast agents for the rapid detection ofS. aureusinfections.