Jo Jeyun, Upadhyay Tulsi, Woods Emily C, Park Ki Wan, Pedowitz Nichole J, Jaworek-Korjakowska Joanna, Wang Sijie, Valdez Tulio A, Fellner Matthias, Bogyo Matthew
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Otolaryngology-Head & Neck Surgery Divisions, Stanford University School of Medicine, Stanford, CA 94305, USA.
bioRxiv. 2023 Dec 12:2023.12.11.571116. doi: 10.1101/2023.12.11.571116.
is a major human pathogen responsible for a wide range of systemic infections. Since its propensity to form biofilms poses formidable challenges for both detection and treatment, tools that can be used to specifically image biofilms are highly valuable for clinical management. Here we describe the development of oxadiazolonebased activity-based probes to target the -specific serine hydrolase FphE. Because this enzyme lacks homologs in other bacteria, it is an ideal target for selective imaging of infections. Using X-ray crystallography, direct cell labeling and mouse models of infection we demonstrate that oxadiazolone-based probes enable specific labeling of 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 (ABPs) and validate FphE as a target for development of imaging contrast agents for the rapid detection of infections.
是一种主要的人类病原体，可导致多种全身感染。由于其形成生物膜的倾向给检测和治疗都带来了巨大挑战，因此可用于特异性成像生物膜的工具对于临床管理具有极高价值。在此，我们描述了基于恶二唑酮的活性探针的开发，以靶向特异性丝氨酸水解酶FphE。由于该酶在其他细菌中缺乏同源物，它是用于感染选择性成像的理想靶点。通过X射线晶体学、直接细胞标记和感染小鼠模型，我们证明基于恶二唑酮的探针能够通过直接共价修饰FphE活性位点丝氨酸来特异性标记细菌。这些结果证明了恶二唑酮亲电试剂在基于活性的探针（ABP）中的效用，并验证FphE作为开发用于快速检测感染的成像造影剂的靶点。
