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6g83

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Crystal structure of M. tuberculosis DprE1 in complex with sPBTZ169 (sulfonylPBTZ)

Structural highlights

6g83 is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DPRE1_MYCTU Involved in the epimerization of decaprenylphosphoryl ribose (DPR) to decaprenylphosphoryl arabinose (DPA) a precursor for arabinan synthesis in mycobacterial cell wall biosynthesis. Probably catalyzes the oxidation at C-2 of decaprenylphosphoryl ribose (DPR) to yield decaprenylphosphoryl 2-keto-ribose (DPX).^[1]

Publication Abstract from PubMed

Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1 thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis As part of the MCZ back-up program we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulphonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ and covalent adducts with the active site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 as compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis.,Piton J, Vocat A, Lupien A, Foo C, Riabova O, Makarov V, Cole ST Antimicrob Agents Chemother. 2018 Jul 16. pii: AAC.00681-18. doi:, 10.1128/AAC.00681-18. PMID:30012754^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mikusova K, Huang H, Yagi T, Holsters M, Vereecke D, D'Haeze W, Scherman MS, Brennan PJ, McNeil MR, Crick DC. Decaprenylphosphoryl arabinofuranose, the donor of the D-arabinofuranosyl residues of mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J Bacteriol. 2005 Dec;187(23):8020-5. PMID:16291675 doi:http://dx.doi.org/10.1128/JB.187.23.8020-8025.2005
↑ Piton J, Vocat A, Lupien A, Foo C, Riabova O, Makarov V, Cole ST. Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2018 Jul 16. pii: AAC.00681-18. doi:, 10.1128/AAC.00681-18. PMID:30012754 doi:http://dx.doi.org/10.1128/AAC.00681-18