Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity.

Mutations in DNA gyrase confer resistance to fluoroquinolones, second-line antibiotics for infections. Identification of new agents that inhibit DNA gyrase ATPase activity is one strategy to overcome this. Here, bioisosteric designs using known inhibitors as templates were employed to define novel inhibitors of DNA gyrase ATPase activity. This yielded the modified compound with improved drug-likeness compared to the template inhibitor that acted as a promising ATPase inhibitor against DNA gyrase. Utilization of compound as a virtual screening template, supported by subsequent biological assays, identified seven further DNA gyrase ATPase inhibitors with IC values in the range of 0.42-3.59 μM. The most active compound showed an IC value of 0.42 μM, 3-fold better than the comparator ATPase inhibitor novobiocin (1.27 μM). Compound showed noncytotoxicity to Caco-2 cells at concentrations up to 76-fold higher than its IC value. Molecular dynamics simulations followed by decomposition energy calculations identified that compound occupies the binding pocket utilized by the adenosine group of the ATP analogue AMPPNP in the DNA gyrase GyrB subunit. The most prominent contribution to the binding of compound to GyrB subunit is made by residue Asp79, which forms two hydrogen bonds with the OH group of this compound and also participates in the binding of AMPPNP. Compound represents a potential new scaffold for further exploration and optimization as a DNA gyrase ATPase inhibitor and candidate anti-tuberculosis agent.