ReviewPost screenStructural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors

•DprE1 is a highly vulnerable drug target.•Complete structural information for DprE1, alone and with ligands, is presented and interpreted.•The main structural determinants for binding DprE1 inhibitors are identified.•Rational design of new inhibitors has been enhanced.

The flavoenzyme DprE1 catalyses a crucial step in arabinan production for cell wall biosynthesis in Mycobacterium tuberculosis and is a highly vulnerable drug target. It was first discovered using benzothiazinones (BTZ): exquisitely potent bactericidal agents that are being developed as drugs to treat tuberculosis. Subsequently, many compounds with diverse scaffolds were found to act as either covalent or noncovalent DprE1 inhibitors. Covalent inhibitors, like the BTZ, are all nitroaromatic compounds that serve as suicide substrates after DprE1-mediated nitroreduction. Here, we describe how high-resolution structures of DprE1, alone and in complex with various ligands, explain enzyme activity and inhibition.