Trefzer, ClaudiaŠkovierová, HenrietaBuroni, SilviaBobovská, AdelaNenci, SimoneMolteni, ElisabettaPojer, FlorencePasca, Maria R.Makarov, VadimCole, Stewart T.Riccardi, GiovannaMikušová, KatarínaJohnsson, Kai2012-01-202012-01-202012-01-20201210.1021/ja211042rhttps://infoscience.epfl.ch/handle/20.500.14299/77017WOS:000301084300044Benzothiazinones (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.Escherichia-ColiTuberculosisNitroreductaseGlutathioneResistanceArabinanThiolsRibosetext::journal::journal article::research article