Fluorescent Benzothiazinone Analogues Efficiently and Selectively Label Dpre1 in Mycobacteria and Actinobacteria
| Autor: | Stewart T. Cole, Jérémie Piton, João Neres, John D. McKinney, Raju Mukherjee, Raphael Sommer, Wilbert Bitter, Vadim Makarov, Astrid M. van der Sar, Neeraj Dhar, Paul J. Dyson, Thierry Laroche |
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| Přispěvatelé: | AII - Infectious diseases, Medical Microbiology and Infection Prevention, Molecular Microbiology, AIMMS |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Fluorescence-lifetime imaging microscopy 030106 microbiology Antitubercular Agents Thiazines Microbial Sensitivity Tests arabinan Biochemistry Fluorescence drug discovery Corynebacterium glutamicum Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Residue (chemistry) SDG 3 - Good Health and Well-being Bacterial Proteins inhibitors Actinomycetales Humans Enzyme Inhibitors Nocardia farcinica Fluorescent Dyes biology Chemistry Cell Membrane Affinity Labels General Medicine Hep G2 Cells biology.organism_classification Fluoresceins Alcohol Oxidoreductases 030104 developmental biology tuberculosis Microscopy Fluorescence Drug Design Mutation Molecular Medicine Lead compound Cysteine |
| Zdroj: | Sommer, R, Neres, J, Piton, J, Dhar, N, van der Sar, A, Mukherjee, R, Laroche, T, Dyson, P J, McKinney, J D, Bitter, W, Makarov, V & Cole, S T 2018, ' Fluorescent Benzothiazinone Analogues Efficiently and Selectively Label Dpre1 in Mycobacteria and Actinobacteria ', Acs chemical biology, vol. 13, no. 11, pp. 3184-3192 . https://doi.org/10.1021/acschembio.8b00790 Acs chemical biology, 13(11), 3184-3192. American Chemical Society ACS chemical biology, 13(11), 3184-3192. American Chemical Society Sommer, R, Neres, J, Piton, J, Dhar, N, van der Sar, A, Mukherjee, R, Laroche, T, Dyson, P J, McKinney, J D, Bitter, W, Makarov, V & Cole, S T 2018, ' Fluorescent Benzothiazinone Analogues Efficiently and Selectively Label Dpre1 in Mycobacteria and Actinobacteria ', ACS chemical biology, vol. 13, no. 11, pp. 3184-3192 . https://doi.org/10.1021/acschembio.8b00790 |
| ISSN: | 1554-8929 |
| DOI: | 10.1021/acschembio.8b00790 |
| Popis: | Benzothiazinones (BTZ) are highly potent bactericidal inhibitors of mycobacteria and the lead compound, BTZ043, and the optimized drug candidate, PBTZ169, have potential for the treatment of tuberculosis. Here, we exploited the tractability of the BTZ scaffold by attaching a range of fluorophores to the 2-substituent of the BTZ ring via short linkers. We show by means of fluorescence imaging that the most advanced derivative, JN108, is capable of efficiently labeling its target, the essential flavoenzyme DprE1, both in cell-free extracts and after purification as well as in growing cells of different actinobacterial species. DprE1 displays a polar localization in Mycobacterium tuberculosis, M. marinum, M. smegmatis, and Nocardia farcinica but not in Corynebacterium glutamicum. Finally, mutation of the cysteine residue in DprE1 in these species, to which BTZ covalently binds, abolishes completely the interaction with JN108, thereby highlighting the specificity of this fluorescent probe. |
| Databáze: | OpenAIRE |
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