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. 1996 Feb;40(2):473–476. doi: 10.1128/aac.40.2.473

Mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase.

M Oram 1, B Dosanjh 1, N A Gormley 1, C V Smith 1, L M Fisher 1, A Maxwell 1, K Duncan 1
PMCID: PMC163138  PMID: 8834902

Abstract

GR122222X is a potent inhibitor of the supercoiling reaction of bacterial DNA gyrase. We show that this compound binds stoichiometrically to inactivate the ATPase activity of a 43-kDa N-terminal fragment of the B subunit and competitively inhibits the binding of a radiolabelled coumarin drug to N-terminal fragments of GyrB. These and other data suggest that GR122222X has a mode of action similar, but not identical, to that of coumarin antibiotics.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ali J. A., Jackson A. P., Howells A. J., Maxwell A. The 43-kilodalton N-terminal fragment of the DNA gyrase B protein hydrolyzes ATP and binds coumarin drugs. Biochemistry. 1993 Mar 16;32(10):2717–2724. doi: 10.1021/bi00061a033. [DOI] [PubMed] [Google Scholar]
  2. Ali J. A., Orphanides G., Maxwell A. Nucleotide binding to the 43-kilodalton N-terminal fragment of the DNA gyrase B protein. Biochemistry. 1995 Aug 1;34(30):9801–9808. doi: 10.1021/bi00030a018. [DOI] [PubMed] [Google Scholar]
  3. Contreras A., Maxwell A. gyrB mutations which confer coumarin resistance also affect DNA supercoiling and ATP hydrolysis by Escherichia coli DNA gyrase. Mol Microbiol. 1992 Jun;6(12):1617–1624. doi: 10.1111/j.1365-2958.1992.tb00886.x. [DOI] [PubMed] [Google Scholar]
  4. Cullen M. E., Wyke A. W., Kuroda R., Fisher L. M. Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones. Antimicrob Agents Chemother. 1989 Jun;33(6):886–894. doi: 10.1128/aac.33.6.886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Drlica K., Coughlin S. Inhibitors of DNA gyrase. Pharmacol Ther. 1989;44(1):107–121. doi: 10.1016/0163-7258(89)90093-4. [DOI] [PubMed] [Google Scholar]
  6. Fisher L. M., Kuroda R., Sakai T. T. Interaction of bleomycin A2 with deoxyribonucleic acid: DNA unwinding and inhibition of bleomycin-induced DNA breakage by cationic thiazole amides related to bleomycin A2. Biochemistry. 1985 Jun 18;24(13):3199–3207. doi: 10.1021/bi00334a019. [DOI] [PubMed] [Google Scholar]
  7. Gellert M., Mizuuchi K., O'Dea M. H., Itoh T., Tomizawa J. I. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc Natl Acad Sci U S A. 1977 Nov;74(11):4772–4776. doi: 10.1073/pnas.74.11.4772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gilbert E. J., Maxwell A. The 24 kDa N-terminal sub-domain of the DNA gyrase B protein binds coumarin drugs. Mol Microbiol. 1994 May;12(3):365–373. doi: 10.1111/j.1365-2958.1994.tb01026.x. [DOI] [PubMed] [Google Scholar]
  9. Goetschi E., Angehrn P., Gmuender H., Hebeisen P., Link H., Masciadri R., Nielsen J. Cyclothialidine and its congeners: a new class of DNA gyrase inhibitors. Pharmacol Ther. 1993 Nov;60(2):367–380. doi: 10.1016/0163-7258(93)90017-8. [DOI] [PubMed] [Google Scholar]
  10. Greenstein M., Speth J. L., Maiese W. M. Mechanism of action of cinodine, a glycocinnamoylspermidine antibiotic. Antimicrob Agents Chemother. 1981 Oct;20(4):425–432. doi: 10.1128/aac.20.4.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hallett P., Grimshaw A. J., Wigley D. B., Maxwell A. Cloning of the DNA gyrase genes under tac promoter control: overproduction of the gyrase A and B proteins. Gene. 1990 Sep 1;93(1):139–142. doi: 10.1016/0378-1119(90)90148-k. [DOI] [PubMed] [Google Scholar]
  12. Lewis R. J., Singh O. M., Smith C. V., Maxwell A., Skarzynski T., Wonacott A. J., Wigley D. B. Crystallization of inhibitor complexes of an N-terminal 24 kDa fragment of the DNA gyrase B protein. J Mol Biol. 1994 Aug 5;241(1):128–130. doi: 10.1006/jmbi.1994.1480. [DOI] [PubMed] [Google Scholar]
  13. Maxwell A. The interaction between coumarin drugs and DNA gyrase. Mol Microbiol. 1993 Aug;9(4):681–686. doi: 10.1111/j.1365-2958.1993.tb01728.x. [DOI] [PubMed] [Google Scholar]
  14. Maxwell A. The molecular basis of quinolone action. J Antimicrob Chemother. 1992 Oct;30(4):409–414. doi: 10.1093/jac/30.4.409. [DOI] [PubMed] [Google Scholar]
  15. McCullough J. E., Muller M. T., Howells A. J., Maxwell A., O'Sullivan J., Summerill R. S., Parker W. L., Wells J. S., Bonner D. P., Fernandes P. B. Clerocidin, a terpenoid antibiotic, inhibits bacterial DNA gyrase. J Antibiot (Tokyo) 1993 Mar;46(3):526–530. doi: 10.7164/antibiotics.46.526. [DOI] [PubMed] [Google Scholar]
  16. Mizuuchi K., Mizuuchi M., O'Dea M. H., Gellert M. Cloning and simplified purification of Escherichia coli DNA gyrase A and B proteins. J Biol Chem. 1984 Jul 25;259(14):9199–9201. [PubMed] [Google Scholar]
  17. Nakada N., Gmünder H., Hirata T., Arisawa M. Mechanism of inhibition of DNA gyrase by cyclothialidine, a novel DNA gyrase inhibitor. Antimicrob Agents Chemother. 1994 Sep;38(9):1966–1973. doi: 10.1128/aac.38.9.1966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nakada N., Shimada H., Hirata T., Aoki Y., Kamiyama T., Watanabe J., Arisawa M. Biological characterization of cyclothialidine, a new DNA gyrase inhibitor. Antimicrob Agents Chemother. 1993 Dec;37(12):2656–2661. doi: 10.1128/aac.37.12.2656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Osburne M. S., Maiese W. M., Greenstein M. In vitro inhibition of bacterial DNA gyrase by cinodine, a glycocinnamoylspermidine antibiotic. Antimicrob Agents Chemother. 1990 Jul;34(7):1450–1452. doi: 10.1128/aac.34.7.1450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Reece R. J., Maxwell A. DNA gyrase: structure and function. Crit Rev Biochem Mol Biol. 1991;26(3-4):335–375. doi: 10.3109/10409239109114072. [DOI] [PubMed] [Google Scholar]
  21. Reece R. J., Maxwell A. Tryptic fragments of the Escherichia coli DNA gyrase A protein. J Biol Chem. 1989 Nov 25;264(33):19648–19653. [PubMed] [Google Scholar]
  22. Rádl S. Structure-activity relationships in DNA gyrase inhibitors. Pharmacol Ther. 1990;48(1):1–17. doi: 10.1016/0163-7258(90)90014-s. [DOI] [PubMed] [Google Scholar]
  23. Staudenbauer W. L., Orr E. DNA gyrase: affinity chromatography on novobiocin-Sepharose and catalytic properties. Nucleic Acids Res. 1981 Aug 11;9(15):3589–3603. doi: 10.1093/nar/9.15.3589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Vizán J. L., Hernández-Chico C., del Castillo I., Moreno F. The peptide antibiotic microcin B17 induces double-strand cleavage of DNA mediated by E. coli DNA gyrase. EMBO J. 1991 Feb;10(2):467–476. doi: 10.1002/j.1460-2075.1991.tb07969.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wigley D. B., Davies G. J., Dodson E. J., Maxwell A., Dodson G. Crystal structure of an N-terminal fragment of the DNA gyrase B protein. Nature. 1991 Jun 20;351(6328):624–629. doi: 10.1038/351624a0. [DOI] [PubMed] [Google Scholar]
  26. Yoshida H., Kojima T., Yamagishi J., Nakamura S. Quinolone-resistant mutations of the gyrA gene of Escherichia coli. Mol Gen Genet. 1988 Jan;211(1):1–7. doi: 10.1007/BF00338386. [DOI] [PubMed] [Google Scholar]
  27. del Castillo I., Vizán J. L., Rodríguez-Sáinz M. C., Moreno F. An unusual mechanism for resistance to the antibiotic coumermycin A1. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8860–8864. doi: 10.1073/pnas.88.19.8860. [DOI] [PMC free article] [PubMed] [Google Scholar]

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