Bacterial DNA gyrase is an important target of
antibacterial agents, including
fluoroquinolones. In most bacterial species,
fluoroquinolones inhibit
DNA gyrase and
topoisomerase IV and cause bacterial cell-death. Other naturally occurring
bacterial DNA gyrase inhibitors, such as
novobiocin, are also known to be effective as
antibacterial agents.
DNA gyrase is an
ATP-dependent
enzyme that acts by creating a transient double-stranded DNA break. It is unique in catalyzing the negative supercoiling of
DNA and is essential for efficient DNA replication, transcription, and recombination.
DNA gyrase is a tetrameric A2B2
protein. The A subunit carries the breakage-reunion active site, whereas the B subunit promotes
ATP hydrolysis. The M.
tuberculosis genome analysis has identified a gyrB-gyrA contig in which gyrA and gyrB encode the A and B subunits, respectively. There is no evidence that M.
tuberculosis has homologs of the
topoisomerase IV, parC and parE genes, which are present in most other bacteria. Newer
fluoroquinolones, including
moxifloxacin and
gatifloxacin, exhibit potent activity against M.
tuberculosis, and show potential to shorten the duration for TB treatment. Resistance to
fluoroquinolones remains uncommon in clinical isolates of M.
tuberculosis. M.
tuberculosis DNA gyrase is thus a validated target for anti-tubercular
drug discovery. Inhibitors of this
enzyme are also active against non-replicating mycobacteria, which might be important for the eradication of persistent organisms. A novel inhibitor of M.
tuberculosis DNA gyrase would be effective against multi-
drug resistant (MDR)-TB, and it could also be effective against
fluoroquinolone-resistant M.
tuberculosis.