This title appears in the Scientific Report :
2014
Please use the identifier:
http://dx.doi.org/10.1074/jbc.M113.522623 in citations.
Please use the identifier: http://hdl.handle.net/2128/8019 in citations.
Benzothiazinones Mediate Killing of Corynebacterineae by Blocking Decaprenyl Phosphate Recycling Involved in Cell Wall Biosynthesis
Benzothiazinones Mediate Killing of Corynebacterineae by Blocking Decaprenyl Phosphate Recycling Involved in Cell Wall Biosynthesis
Benzothiazinones (BTZs) are a new class of sulfur containing heterocyclic compounds that target DprE1, an oxidoreductase involved in the epimerization of decaprenyl-phosphoribose (DPR) to decaprenyl-phosphoarabinose (DPA) in the Corynebacterineae, such as Corynebacterium glutamicum and Mycobacterium...
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Personal Name(s): | Grover, S. (Corresponding Author) |
---|---|
Alderwick, L. J. / Mishra, A. K. / Krumbach, K. / Marienhagen, J. / Eggeling, L. / Bhatt, A. / Besra, G. S. | |
Contributing Institute: |
Biotechnologie; IBG-1 |
Published in: | The @journal of biological chemistry, 289 (2014) 9, S. 6177 - 6187 |
Imprint: |
Bethesda, Md.
Soc.
2014
|
DOI: |
10.1074/jbc.M113.522623 |
PubMed ID: |
24446451 |
Document Type: |
Journal Article |
Research Program: |
ohne Topic |
Link: |
OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/8019 in citations.
Benzothiazinones (BTZs) are a new class of sulfur containing heterocyclic compounds that target DprE1, an oxidoreductase involved in the epimerization of decaprenyl-phosphoribose (DPR) to decaprenyl-phosphoarabinose (DPA) in the Corynebacterineae, such as Corynebacterium glutamicum and Mycobacterium tuberculosis. As a result, BTZ inhibition leads to inhibition of cell wall arabinan biosynthesis. Previous studies have demonstrated the essentiality of dprE1. In contrast, Cg-UbiA a ribosyltransferase, which catalyzes the first step of DPR biosynthesis prior to DprE1, when genetically disrupted, produced a viable mutant, suggesting that although BTZ biochemically targets DprE1, killing also occurs through chemical synthetic lethality, presumably through the lack of decaprenyl phosphate recycling. To test this hypothesis, a derivative of BTZ, BTZ043, was examined in detail against C. glutamicum and C. glutamicum::ubiA. The wild type strain was sensitive to BTZ043; however, C. glutamicum::ubiA was found to be resistant, despite possessing a functional DprE1. When the gene encoding C. glutamicum Z-decaprenyl-diphosphate synthase (NCgl2203) was overexpressed in wild type C. glutamicum, resistance to BTZ043 was further increased. This data demonstrates that in the presence of BTZ, the bacilli accumulate DPR and fail to recycle decaprenyl phosphate, which results in the depletion of decaprenyl phosphate and ultimately leads to cell death. |