Structural Aspects of Mycobacterium tuberculosis DNA Gyrase Targeted by Novel Bacterial Topoisomerase Inhibitors

In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of Mycobacterium tuberculosis DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of M. tuberculosis DNA gyrase in complex with DNA and compound 5 from this NBTI series reveals the binding mode of an NBTI in the GyrA binding pocket and confirms the presence and importance of halogen bonding for the excellent on-target potency. In addition, we have shown that compound 5 is a promising M. tuberculosisDNA gyrase inhibitor, with an IC50 for M. tuberculosisgyrase of 0.096 µM, and it has potent activity against M. tuberculosis, with an IC50 of 0.165 µM.