Abstract
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.
Keywords: Type II topoisomerase, supercoiling, decatenate, quinolones, coumarin, simocyclinones
Infectious Disorders - Drug Targets
Title: Mycobacterium tuberculosis DNA Gyrase as a Target for Drug Discovery
Volume: 7 Issue: 2
Author(s): Khisimuzi Mdluli and Zhenkun Ma
Affiliation:
Keywords: Type II topoisomerase, supercoiling, decatenate, quinolones, coumarin, simocyclinones
Abstract: 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.
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Cite this article as:
Khisimuzi Mdluli and Zhenkun Ma , Mycobacterium tuberculosis DNA Gyrase as a Target for Drug Discovery, Infectious Disorders - Drug Targets 2007; 7 (2) . https://dx.doi.org/10.2174/187152607781001763
DOI https://dx.doi.org/10.2174/187152607781001763 |
Print ISSN 1871-5265 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3989 |
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