The Naphthoquinone Diospyrin Is an Inhibitor of DNA Gyrase with a Novel Mechanism of Action

Background: New antibacterial compounds are urgently needed; DNA gyrase is a well-validated target. Results: Diospyrin and other naphthoquinones inhibit DNA gyrase by binding to a novel site in the B subunit. Conclusion: Naphthoquinones are inhibitors of gyrase with a novel mechanism of action. Significance: Naphthoquinones have potential as antibacterial compounds against TB. Tuberculosis and other bacterial diseases represent a significant threat to human health. The DNA topoisomerases are excellent targets for chemotherapy, and DNA gyrase in particular is a well-validated target for antibacterial agents. Naphthoquinones (e.g. diospyrin and 7-methyljuglone) have been shown to have therapeutic potential, particularly against Mycobacterium tuberculosis. We have found that these compounds are inhibitors of the supercoiling reaction catalyzed by M. tuberculosis gyrase and other gyrases. Our evidence strongly suggests that the compounds bind to the N-terminal domain of GyrB, which contains the ATPase active site, but are not competitive inhibitors of the ATPase reaction. We propose that naphthoquinones bind to GyrB at a novel site close to the ATPase site. This novel mode of action could be exploited to develop new antibacterial agents.

• Publication year

  2012

• Venue

  Journal of Biological Chemistry

• Publication date

  2012-12-28

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M112.419069PMID 23275348PMCID 3576119
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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