Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 134, Issue 2, Pages 912-915Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja211042r
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Funding
- European Community [260872]
- Swiss National Science Foundation (SNF)
- Scientific Grant Agency of the Ministry of Education of Slovak Republic [VEGA 1/0508/10]
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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-beta-D-ribofuranose 2'-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.
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