Published in
American Association for the Advancement of Science, Science Translational Medicine, 150(4), 2012
DOI: 10.1126/scitranslmed.3004395
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- [www.ncbi.nlm.nih.gov] | PDF
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- [wrap.warwick.ac.uk]
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- [www.researchgate.net] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
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Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis
,
Florence Pojer,
Elisabetta Molteni,
Laurent R. Chiarelli ,
Stefanie Boy-Röttger,
Neeraj Dhar,
Silvia Buroni,
Elizabeth Fullam,
Giulia Degiacomi,
Anna Paola Lucarelli,
Randy J. Read,
Giuseppe Zanoni,
Dale E. Edmondson,
Edda De Rossi,
Maria Rosalia Pasca
and other authors.
Full text: Download
Abstract
BTZ043, a tuberculosis drug candidate with nanomolar whole-cell activity, targets the DprE1 enzyme of the essential decaprenylphosphoryl-β-D-ribofuranose-2′-epimerase thus blocking biosynthesis of arabinans, vital cell-wall components of mycobacteria. Crystal structures of DprE1, in its native form and in complex with BTZ043, unambiguously reveal formation of a semimercaptal adduct between the drug and an active-site cysteine, as well as contacts to a neighbouring catalytic lysine residue. Kinetic studies confirm BTZ043 as a mechanism-based, covalent inhibitor. This explains the exquisite potency of BTZ043, which, when fluorescently labelled, localizes DprE1 at the poles of growing bacteria. Menaquinone can reoxidize the FAD cofactor in DprE1 and may be the natural electron acceptor for this reaction in the cell. Our structural and kinetic analysis provides both insight into a critical epimerization reaction and a platform for structure-based design of improved inhibitors. Surprisingly, given the colossal tuberculosis burden globally, BTZ043 is the only new drug candidate to have been co-crystallized with its target.