Benzothiazinones Are Suicide Inhibitors of Mycobacterial Decaprenylphosphoryl-尾-d-ribofuranose 2鈥?Oxidase DprE1

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• 作者：Claudia Trefzer ; Henrieta 艩kovierov谩 ; Silvia Buroni ; Adela Bobovsk谩 ; Simone Nenci ; Elisabetta Molteni ; Florence Pojer ; Maria R. Pasca ; Vadim Makarov ; Stewart T. Cole ; Giovanna Riccardi ; Katar铆na Miku拧ov谩 ; Kai Johnsson
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：January 18, 2012
• 年：2012
• 卷：134
• 期：2
• 页码：912-915
• 全文大小：254K
• 年卷期：v.134,no.2(January 18, 2012)
• ISSN：1520-5126

文摘

Benzothiazinones (BTZs) are antituberculosis drug candidates with nanomolar bactericidal activity against tubercle bacilli. Here we demonstrate that BTZs are suicide substrates of the FAD-dependent decaprenylphosphoryl-尾-d-ribofuranose 2鈥?oxidase DprE1, an enzyme involved in cell-wall biogenesis. BTZs are reduced by DprE1 to an electrophile, which then reacts in a near-quantitative manner with an active-site cysteine of DprE1, thus providing a rationale for the extraordinary potency of BTZs. Mutant DprE1 enzymes from BTZ-resistant strains reduce BTZs to inert metabolites while avoiding covalent inactivation. Our results explain the basis for drug sensitivity and resistance to an exceptionally potent class of antituberculosis agents.