Molecular Probes for the Determination of Subcellular Compound Exposure Profiles in Gram-Negative Bacteria
2018
The Gram-negative
cell envelopepresents a formidable barrier to
xenobiotics, and achieving sufficient compound
exposureinside the cell is a key challenge for the discovery of new antibiotics. To provide insight on the molecular determinants governing compound
exposurein
Gram-negative bacteria, we developed a methodology leveraging a cyclooctyne-based bioorthogonal probe to assess compartment-specific compound
exposure. This probe can be selectively localized to the periplasmic or cytoplasmic compartments of
Gram-negative bacteria. Once localized, the probe is used to test
azide-containing compounds for
exposurewithin each compartment by quantifying the formation of click-reaction products by mass spectrometry. We demonstrate this approach is an accurate and sensitive method of determining compartment-specific compound
exposureprofiles. We then apply this technology to study the compartment-specific
exposureprofiles of a small panel of
azide-bearing compounds with known permeability characteristics i...
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