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Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis
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(2012) Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis. Science Translational Medicine, Vol.4 (No.150). Article no. 150ra121. doi:10.1126/scitranslmed.3004395 ISSN 1946-6234.
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Official URL: http://dx.doi.org/10.1126/scitranslmed.3004395
Abstract
The benzothiazinone BTZ043 is a tuberculosis drug candidate with nanomolar whole-cell activity. BTZ043 targets the DprE1 catalytic component of the essential enzyme decaprenylphosphoryl-β-D-ribofuranose-2′-epimerase, thus blocking biosynthesis of arabinans, vital components of mycobacterial cell walls. Crystal structures of DprE1, in its native form and in a complex with BTZ043, reveal formation of a semimercaptal adduct between the drug and an active-site cysteine, as well as contacts to a neighboring catalytic lysine residue. Kinetic studies confirm that BTZ043 is a mechanism-based, covalent inhibitor. This explains the exquisite potency of BTZ043, which, when fluorescently labeled, localizes DprE1 at the poles of growing bacteria. Menaquinone can reoxidize the flavin adenine dinucleotide cofactor in DprE1 and may be the natural electron acceptor for this reaction in the mycobacterium. Our structural and kinetic analysis provides both insight into a critical epimerization reaction and a platform for structure-based design of improved inhibitors.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Science Translational Medicine | ||||
Publisher: | American Association for the Advancement of Science | ||||
ISSN: | 1946-6234 | ||||
Official Date: | 2012 | ||||
Dates: |
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Volume: | Vol.4 | ||||
Number: | No.150 | ||||
Page Range: | Article no. 150ra121 | ||||
DOI: | 10.1126/scitranslmed.3004395 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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