Fluorescent Triazole Urea Activity-Based Probes for the Single-Cell Phenotypic Characterization of Staphylococcus aureus.,Angewandte Chemie International Edition

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Fluorescent Triazole Urea Activity-Based Probes for the Single-Cell Phenotypic Characterization of Staphylococcus aureus.
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2019-03-22 , DOI: 10.1002/anie.201900511
Linhai Chen _{1,

2} , Laura J Keller ₃ , Edward Cordasco ₁ , Matthew Bogyo _{1,

4} , Christian S Lentz _{1,

5}

Affiliation

Phenotypically distinct cellular (sub)populations are clinically relevant for the virulence and antibiotic resistance of a bacterial pathogen, but functionally different cells are usually indistinguishable from each other. Herein, we introduce fluorescent activity-based probes as chemical tools for the single-cell phenotypic characterization of enzyme activity levels in Staphylococcus aureus. We screened a 1,2,3-triazole urea library to identify selective inhibitors of fluorophosphonate-binding serine hydrolases and lipases in S. aureus and synthesized target-selective activity-based probes. Molecular imaging and activity-based protein profiling studies with these probes revealed a dynamic network within this enzyme family involving compensatory regulation of specific family members and exposed single-cell phenotypic heterogeneity. We propose the labeling of enzymatic activities by chemical probes as a generalizable method for the phenotyping of bacterial cells at the population and single-cell level.

中文翻译：

基于荧光三唑尿素活性的探针，用于金黄色葡萄球菌的单细胞表型表征。

表型不同的细胞（亚）群在临床上与细菌病原体的毒力和抗生素耐药性相关，但功能不同的细胞通常彼此无法区分。在此，我们引入基于荧光活性的探针作为化学工具，用于金黄色葡萄球菌酶活性水平的单细胞表型表征。我们筛选了 1,2,3-三唑尿素文库，以鉴定金黄色葡萄球菌中氟膦酸结合丝氨酸水解酶和脂肪酶的选择性抑制剂，并合成了基于靶标选择性活性的探针。使用这些探针进行的分子成像和基于活性的蛋白质分析研究揭示了该酶家族内的动态网络，涉及特定家族成员的补偿性调节和暴露的单细胞表型异质性。我们建议通过化学探针标记酶活性作为在群体和单细胞水平上对细菌细胞表型进行概括的方法。

更新日期：2019-03-22

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