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조제윤Jeyun Jo

Stanford University School of Medicine

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J. Am. Chem. Soc., Feb 27 2024, | https://doi.org/10.1021/jacs.3c13974 Development of Oxadiazolone Activity-Based Probes Targeting FphE for Specific Detection of Staphylococcus aureus Infections

Jeyun Jo ¹, Tulsi Upadhyay ¹, Emily C Woods ¹, Ki Wan Park ², Nichole J Pedowitz ¹, Joanna Jaworek-Korjakowska ³, Sijie Wang ¹, Tulio A Valdez ², Matthias Fellner ⁴, Matthew Bogyo ^1,5

¹Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States.

²Department of Otolaryngology-Head & Neck Surgery Divisions, Stanford University School of Medicine, Stanford, California 94305, United States.

³Department of Automatic Control and Robotics, AGH University of Krakow, Krakow 30-059, Poland.

⁴Biochemistry Department, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.

⁵Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, United States.

J.J. and T.U. contributed equally.

Corresponding Author : Matthew Bogyo

Abstract

Staphylococcus aureus ( S. aureus) is a major human pathogen that is responsible for a wide range of systemic infections. Since its propensity to form biofilms in vivo poses formidable challenges for both detection and treatment, tools that can be used to specifically image S. aureus biofilms are highly valuable for clinical management. Here, we describe the development of oxadiazolone-based activity-based probes to target the S. aureus-specific serine hydrolase FphE. Because this enzyme lacks homologues in other bacteria, it is an ideal target for selective imaging of S. aureus infections. Using X-ray crystallography, direct cell labeling, and mouse models of infection, we demonstrate that oxadiazolone-based probes enable specific labeling of S. aureus bacteria 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 of S. aureus infections.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-03-05)
연구진국외 연구진
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