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

Abstract

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