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Angew Chem Int Ed Engl. 2019 Nov 29. doi: 10.1002/anie.201912075. [Epub ahead of print]

Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome.

Author information

1
Technische Universitat Munchen, Chemistry, Lichtenbergstrasse 4, 85748, Garching bei Munchen, GERMANY.

Abstract

Rapid development of bacterial resistance has led to an urgent need to find new druggable targets for antibiotics. In this context, residue-specific chemoproteomic approaches enable proteome-wide identification of binding sites for covalent inhibitors. Here, we describe isotopically labeled desthiobiotin azide (isoDTB) tags that were easily synthesized, shortened the chemoproteomic workflow and allowed an increased coverage of cysteines in bacterial systems. We quantified 59% of all cysteines in essential proteins in Staphylococcus aureus and discovered 88 cysteines with high reactivity, which correlates with functional importance. Furthermore, we identified 268 cysteines that are engaged by covalent ligands. We verified inhibition of HMG-CoA synthase, which will allow addressing the bacterial mevalonate pathway through a new target. Overall, a broad map of the bacterial cysteinome was obtained, which will facilitate the development of antibiotics with novel modes-of-action.

KEYWORDS:

Antibiotics; Covalent Inhibitors; Isotopic labeling; Proteomics; protein modifications

PMID:
31782878
DOI:
10.1002/anie.201912075

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