Novel Mycobacterial Inhibitors for DNA Gyrase

DNA gyrase is a type II topoisomerase that acts by creating a transient double-stranded DNA break. DNA gyrase catalyzes negative supercoiling of DNA at the expense of ATP hydrolysis. DNA gyrase is essential for efficient DNA replication, transcription, and recombination in bacteria but is absent from higher eukaryotes, making it an attractive target for drug discovery. Fluoroquinolones and other naturally occurring bacterial DNA gyrase inhibitors, such as novobiocin, are proven clinically as antibacterial agents. Resistance to fluoroquinolones remains uncommon in clinical isolates of Mycobacterium tuberculosis (Mtb) which therefore makes DNA Gyrase a validated target for anti-tubercular drug discovery.

Interstingly, Mtb Gyrase and Bacterial primase have common structural features/motifs. Inhibitors we found using NMR-fragment based and virtual screening bind to the amino acid residues near the Toprim domain of DnaG primase of Mtb. Interstignly, few small-molecules inhibit also Mtb Gyrase presumably through a related TOPRIM domain.

Structure-activity relationship (SAR) studies of newly synthesized small molecules revealed that attaching carbonyl groups to the Indole ring significantly improves inhibition of Mtb Gyrase. Some of the compounds present comparable inhibition with respect to standard antibiotic Gatifloxacin. Thus, indole containing carboxylic acid and carbonyl ester represent promising new anti-tuberculous agents.