title: The naphthoquinone diospyrin is an inhibitor of DNA gyrase with a novel mechanism of action.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, United Kingdom.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Karkare
authors.forename: Terence T H
authors.initials: TT
authors.lastname: Chung
authors.forename: Frederic
authors.initials: F
authors.lastname: Collin
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Mitchenall
authors.forename: Adam R
authors.initials: AR
authors.lastname: McKay
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Greive
authors.forename: Jacobus J M
authors.initials: JJ
authors.lastname: Meyer
authors.forename: Namrita
authors.initials: N
authors.lastname: Lall
authors.forename: Anthony
authors.initials: A
authors.lastname: Maxwell
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000890:Anti-Infective Agents / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D004247:DNA / Q000235:genetics; D027081:DNA Gyrase / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry / Q000379:methods; D008956:Models, Chemical; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D009285:Naphthoquinones / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000890:Anti-Infective Agents; D009285:Naphthoquinones; D000255:Adenosine Triphosphate; D004247:DNA; D027081:DNA Gyrase; C043546:diospyrin