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Single-cell phenotypic characterization of Staphylococcus aureus with fluorescent triazole urea activity-based probes.
Chen, Linhai Keller, Laura J Cordasco, Edward A Bogyo, Matthew Lentz, Christian S
Chen, Linhai
Keller, Laura J
Cordasco, Edward A
Bogyo, Matthew
Lentz, Christian S
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2019-02-15
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Phenotypically distinct cellular (sub)populations are clinically relevant for virulence and antibiotic resistance of a bacterial pathogen, but functionally different cells are usually indistinguishable from each other. Here, we introduce fluorescent activity-based probes as chemical tools for 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 chemical probe labeling of enzymatic activities as a generalizable method for phenotyping of bacterial cells at the population and single-cell level.
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Angew Chem Int Ed Engl. 2019 Feb 15. doi: 10.1002/anie.201900511.
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PMC6456404
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1521-3773
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Attribution-NonCommercial-ShareAlike 4.0 International