Review Article
Full Access
Molecular mechanisms of durg inhibition of DNA gyrase
Richard J. Lewis,
Francis T. F. Tsai,
Dale B. Wigley,
Richard J. Lewis
Laboratory of Molecular Biophysics. The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Search for more papers by this authorFrancis T. F. Tsai
Laboratory of Molecular Biophysics. The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Search for more papers by this authorCorresponding Author
Dale B. Wigley
Laboratory of Molecular Biophysics. The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Laboratory of Molecular Biophysics. The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.Search for more papers by this authorRichard J. Lewis,
Francis T. F. Tsai,
Dale B. Wigley,
Richard J. Lewis
Laboratory of Molecular Biophysics. The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Search for more papers by this authorFrancis T. F. Tsai
Laboratory of Molecular Biophysics. The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Search for more papers by this authorCorresponding Author
Dale B. Wigley
Laboratory of Molecular Biophysics. The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Laboratory of Molecular Biophysics. The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.Search for more papers by this authorAbstract
DNA gyrase, an enzyme unique to prokaryotes, has been implicated in almost all processes that involve DNA. Although efficient inhibitors of this protein have been known for more than 20 years, none of them have enjoyed prolonged pharmaceutical success. It is only recently that the mechanisms of inhibition for some of these classes of drugs have been established unequivocally by X-ray crystallography. It is hoped that this detailed structural information will assist the design of novel, effective inhibitors of DNA gyrase.
References
- 1 Wang, J. C. (1985). DNA topoisomerases. Ann. Rev. Biochem. 54, 665–697.
- 2 Reece, R. J. and Maxwell, A. (1991). DNA gyrase: structure and function. Crit. Rev. Biochem. Mol. Biol. 26, 335–375.
- 3 Gellert, M., Mizuuchi, K., O' Dea, M. H. and Nash, H. A. (1976). DNA gyrase: an enzyme that introduces superhelical turns into DNA. Proc. Natl Acad. Sci. USA 73, 3872–3876.
- 4 Caron, P. and Wang, J. C. (1995). Alignment of primary sequences of DNA topoisomerases. In DNA Topoisomerases and Their Applications in Pharmacology. Advances in Pharmacology 29A, (ed. L. Liu), pp. 271–297. Academic Press.
- 5 Sugino, A. and Cozzarelli, N. R. (1980). The intrinsic ATPase of DNA gyrase. J. Biol. Chem. 255, 6299–6306.
- 6 Klevan, L. and Wang, J. C. (1980). A DNA-DNA gyrase complex containing 140 base pairs of DNA and an α2β2 protein core. Biochemistry 19, 5229–5234.
- 7 Krueger, S. et al. (1990). Neutron and light-scattering studies of DNA gyrase and its complex with DNA. J. Mol. Biol. 211, 211–220.
- 8 Kirchausen, T., Wang,J. C. and Harrison, S. C. (1985). DNA gyrase and its complexes with DNA: direct observation by electron microscopy. Cell 41, 933–943.
- 9 Higgins, N. P., Peebles, C. L., Sugino, A. and Cozzarelli, N. R. (1978). Purification of the subunits of Escherichia coli DNA gyrase and reconstitution of enzymatic activity. Proc. Natl Acad. Sci. USA 75, 1773–1777.
- 10 Gellert, M., Mizuuchi, K., O'Dea, M. H., Itoh, T. and Tomizawa, J. (1977). Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc. Natl Acad. Sci. USA 74, 4772–4776.
- 11 Sugino, A., Peebles, C. L., Kreuzer,K. N. and Cozzarelli, N. R. (1977). Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proc. Natl Acad. Sci. USA 74, 4767–4771.
- 12 Gellert, M., O'Dea, M. H., Itoh, T. and Tomizawa, J. (1976). Novobiocin and coumermycin inhibit DNA supercoiling catalysed by DNA gyrase. Proc. Natl Acad. Sci. USA 73, 4474–4478.
- 13 Mizuuchi, K. O'Dea, M. H. and Gellert, M. (1978). DNA gyrase, subunit structure and ATPase activity of the purified enzyme. Proc. Natl Acad. Sci. USA 75, 5960–5963.
- 14 Maxwell, A. and Gellert, M. (1984). The DNA dependence of the ATPase activity of DNA gyrase. J. Biol. Chem. 259, 14472–14480.
- 15 Reece, R. J. and Maxwell, A. (1989). Tryptic fragments of the Escherichia coli DNA gyrase A protein. J. Biol. Chem. 264, 19648–19653.
- 16 Reece, R. J. and Maxwell, A. (1991). Probing the limits of the DNA breakage-reunion domain of the Escherichia coli DNA gyrase A protein. J. Biol. Chem. 266, 3540–3546.
- 17 Reece, R. J. and Maxwell, A. (1991). The C-terminal domain of the Escherichia coli DNA gyrase A subunit is a DNA-binding protein. Nucleic Acids Res. 19, 1399–1405.
- 18 Ali, J. A., Jackson, A. P., Howells,A. J. and Maxwell, A. (1993). The 43 kDa N-terminal fragment of the gyrase B protein hydrolyses ATP and binds coumarin drugs. Biochemistry 32, 2717–2724.
- 19 Brown, P. O., Peebles,C. L. and Cozzarelli, N. R. (1979). A topoisomerase from Escherichia coli related to DNA gyrase. Proc. Natl Acad. Sci. USA 76, 6110–6114.
- 20 Gellert, M., Fisher,L. M. and O'Dea, M. H. (1979). DNA gyrase: purification of and catalytic properties of a fragment of gyrase B protein. Proc. Natl Acad. Sci. USA 76, 6289–6293.
- 21 Drlica, K. and Franco, R. J. 1988 Inhibitors of DNA topoisomerases. Biochemistry 27, 2253–2259.
- 22 Baquero, F., Bouanchauld, D., Martinez-Pérez, M. C. and Fernandez, C. (1978). Microcin plasmids; a group of extrachromosomal elements coding for low molecular weight antibiotics in Escherichia coli. J. Bacteriol. 135, 342–347.
- 23 Bernard, P. and Couturier, M. (1992). Cell killing by the F-plasmid ccdB protein involves poisoning of DNA-topoisomerase-ll complexes. J. Mol. Biol. 226, 735–745.
- 24 Hoeksema, H., Johnson,J. L. and Hinman, J. W. (1955). Structural studies on streptonivicin, a new antibiotic. J. Am. Chem. Soc. 78, 6710–6711.
- 25 Kuo, M. S., Yurek, D. A., Chirby, D. G., Cialdella,J. I. and Marshall, V. P. (1991). Microbial O-carbamoylation of novobiocin. J. Antibiot. 44, 1096–1100.
- 26 Nakada, N. et al. (1993). Biological characterisation of cyclothialidine, a new DNA gyrase inhibitor. Antimicrob. Agents Chemother. 37, 2656–2661.
- 27 Wigley, D. B., Davies, G. J., Dodson, E. J., Maxwell, A. and Dodson, G. (1991). Crystal structure of the N-terminal domain of the DNA gyrase B protein. Nature 351, 624–629.
- 28 Sugino, A., Higgins, N. P., Brown, P. O., Peebles,C. L. and Cozzarelli, N. R. (1978). Energy coupling in DNA gyrase and the mechanism of action of novobiocin. Proc. Natl Acad. Sci. USA 75, 4838–4842.
- 29 Staudenbauer, W. L. and Orr, E. (1981). DNA gyrase: affinity chromatography on novobiocin-sepharose and catalytic properties. Nucleic Acids Res. 9, 3589–3603.
- 30 Nakada, N., Gmuender, H., Hirata, T. and Arisawa, M. (1994). Mechanism of inhibition of DNA gyrase by cyclothialidine, a novel DNA gyrase inhibitor. Antimicrob. Agents Chemother. 38, 1966–1973.
- 31 del Castillo, I., Vizán, J. L., Rodríguez-Saínz, M. C. and Moreno, F. (1991). An unusual mechanism for resistance to the antibiotic coumermycin A1. Proc. Natl Acad. Sci. USA 88, 8860–8864.
- 32 Holmes, M. L. and Dyall-Smith, M. L. (1991). Mutations in DNA gyrase result in novobiocin resistance in halophilic archaebacteria. J. Bacteriol. 173, 642–648.
- 33 Contreras, A. and Maxwell, A. (1992). gyrB mutations which confer coumarin resistance also affect DNA supercoiling and ATP hydrolysis by Escherichia coli DNA gyrase. Mol. Microbiol. 6, 1617–1624.
- 34 Samuels, D. S., Marconi, R. T., Huang,W. M. and Garon, C. F. (1994). gyrB mutations in coumermycin A1-resistant Borrelia burgdorferi J. Bacteriol. 176, 3072–3075.
- 35 Sugino, A., Peebles, C. L., Kreuzer,K. N. and Cozzarelli, N. R. (1977). Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proc. Natl Acad. Sci. USA 74, 4767–4771.
- 36 Kirkegaard, K. and Wang, J. C. (1981). Mapping the topography of DNA wrapped around gyrase by nucleolytic and chemical probing of complexes of unique DNA sequences. Cell 23, 721–729.
- 37 Tse, Y.-C., Kirkegaard, K. and Wang, J. C. (1980).Covalent bonds between protein and DNA: formation of phosphotyrosine linkage between certain DNA topoisomerases and DNA. J. Biol. Chem. 255, 5560–5565.
- 38 Morrison, A. and Cozzarelli, N. R. (1979). Site-specific cleavage of DNA by E. coli. Cell 17, 175–184.
- 39 Lockshon, D. and Morris, D. R. (1985). Sites of reaction of Escherichia coli DNA gyrase on pBR322 in vivo as revealed by oxolinic acid-induced plasmid linearization. J. Mol. Biol. 181, 63–74.
- 40 Fisher, L. M., Mizuuchi, K., O'Dea, M. H., Ohmori, H. and Gellert, M. (1981). Site-specific interaction of DNA gyrase with DNA. Proc. Natl Acad. Sci. USA 78, 4165–4169.
- 41 Sugino, A., Higgins,N. P. and Cozzarelli, N. R. (1980). DNA gyrase subunit stoichiometry and the covalent attachment of subunit A to DNA during DNA cleavage. Nucleic Acids Res. 8, 3865–3874.
- 42 Morrison, A. and Cozzarelli, N. R. (1981). Contacts between DNA gyrase and its binding site on DNA: features of symmetry and asymmetry revelaed by protection from nucleases. Proc. Natl Acad. Sci. USA 78, 1416–1420.
- 43 Fisher, L. M. Barot, H. A. and Cullen, M. E. (1986). DNA gyrase complex with DNA: determinants for site-specific DNA breakage. EMBO J. 45, 1411–1418.
- 44 Shen, L. L. and Pernet, A. G. (1985). Mechanism of inhibition of DNA gyrase by analogues of nalidixic acid: the target of the drugs is DNA gyrase. Proc. Natl Acad. Sci. USA 82, 307–311.
- 45 Yonezawa, M., Takahata, M., Matsubara, N., Watanabe, Y. and Narita, H. (1995). DNA gyrase gyrA mutations in quinolone-resistant clinical isolates of Pseudomonas aeruginosa Antimicrob. Agents Chemother. 39, 1970–1972.
- 46 Yamagishi, J., Yoshida, H., Yamyoshi, M. and Nakamura, S. (1986). Nalidixic acid-resistant mutations of the gyrB gene of Escherichia coli Mol. Gen. Genet. 204, 367–373.
- 47 Ito, H., Yoshida, H., Bogakishonai, M., Niga, T., Hattori, H. and Nakamura, S. (1994). Quinolone resistance mutations in the DNA gyrase gyrA and gyrB genes of Staphylococcus aureus Antimicrob. Agents Chemother. 39, 1970–1972.
- 48 Willmott, C. J. R., Critchlow, S. E., Eperon,I. C. and Maxwell, A. (1994). The complex of DNA gyrase and quinolone drugs with DNA forms a barrier to transcription by RNA polymerase. J. Mol. Biol. 242, 351–363.
- 49 Rádl, S. (1990). Structure-activity relationships in DNA gyrase inhibitors. Pharmac. Ther. 48, 1–17.
- 50 Yorgey, P. et al. (1994). Posttranslational modifications of microcin B17 define an additional class of DNA gyrase inhibitor. Proc. Natl Acad. Sci. USA 91, 4519–4523.
- 51 Vizán, J. L., Hernandez-Chico, C., del Castillo, I. and Moreno, F. (1991). The peptide antibiotic microcin B17 induces double-stranded cleavage of DNA mediated by E. coli DNA gyrase. EMBOJ. 10, 467–476.
- 52 Maki, S., Takiguchi, S., Horiuchi, T., Sekimizu, K. and Miki, T. (1996). Partner switching mechanisms in inactivation and rejuvenation of Escherichia coli DNA gyrase by F plasmid proteins LetD (CcdB) and LetA (CcdA). J. Mol. Biol. 256, 473–482.
- 53 Bernard, P. et al. (1993). The F plasmid ccdB protein induces efficient ATP-dependent DNA cleavage by gyrase. J. Mol. Biol. 234, 534–541.
- 54 Murayama, N. et al. (1996). Evidence for involvement of Escherichia coli genes pmbA, csrA and a previousy unrecognised gene tldD, in the control of DNA gyrase by letD ccdB) of sex factor ( F. J. Mol. Biol. 256, 483–502.
- 55 Maxwell, A. (1993). The interaction between coumarin drugs and DNA gyrase. Mol. Microbiol. 9, 681–686.
- 56 Berger, J. and Batcho, A. D. (1978). Coumarin-glycoside antibiotics. J. Chromatogr. Libr. 15, 101–156.
- 57 Morris, A. & Russell, A. D. (1971). Mode of action of novobiocin. Prog. Med. Chem. 8, 39–59.
- 58 Orr, L., Fairweather, N. F., Holland,I. B. and Pritchard, R. H. (1979). Isolation and characterisation of a strain carrying a conditional lethal mutation in the cou gene of Escherichia coli K12. Mol. Gen. Genet. 177, 103–112.
- 59 Thiara, A. S. and Cundliffe, E. (1993). Expression and analysis of 2 gyrB genes from the novobiocin producer Streptomyces sphaeroides, Mol. Microbiol. 8, 495–506.
- 60 Celia, H. et al. (1994). Three-dimensional model of Escherichia coli gyrase-B subunit crystallised in 2-dimensions on novobiocin-linked phospholipid films. J. Mol. Biol. 236, 618–628.
- 61 Gilbert, E. J. and Maxwell, A. (1994). The 24 kDa N-terminal sub-domain of the DNA gyrase B protein binds coumarin drugs. Mol. Microbiol. 12, 365–373.
- 62 Lewis, R. J. et al. (1994). Crystallisation of inhibitor complexes of an N-terminal 24 kDa fragment of the DNA gyrase B protein. J. Mol. Biol. 241, 128–130.
- 63 Lewis, R. J. et al. (1996). The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray Crystallography. EMBO J. 15, 1412–1420.
- 64 Hooper, D. C., Wolfson, J. S., McHugh, G. L., Winters,M. B. and Schwarz, M. N. (1982). Effect of novobiocin, coumermycin A1, clorobiocin, and their analogues on Escherichia coli DNA gyrase and bacterial growth. Antimicrob. Agents Chemother. 22, 662–671.
- 65 Götschi, E. et al. (1993). Cyclothialidine and its congeners: a new class of DNA gyrase inhibitors. Pharmac. Ther. 60, 367–380.
- 66 Oram, M. et al. (1996). Mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase. Antimicrob. Agents Chemother. 40, 473–476.
- 67 Watanabe, J. et al. (1994). Cyclothialidine, a novel DNA gyrase inhibitor. I. Screening, taxonomy, fermentation and biological activity. J. Antibiotics 47, 32–36
- 68 Nakada, N., Gmünder, H., Hirata, T. and Arisawa, M. (1994). Mechanism of inhibition of DNA gyrase by cyclothialidine, a novel DNA gyrase inhibitor. Antimicrob. Agents Chemother. 38, 1966–1973
- 69 Fersht, A. R. (1985). Enzyme Structure and Mechanism. W. H. Freeman and Company, New York.
- 70 Althaus, I. W., Dolak, L. and Reusser, F. (1988). Coumarins as inhibitors of bacterial DNA gyrase. J. Antibiot. 41, 373–376.
- 71 Sutcliffe, J. et al. (1992). 3-Carbamoyl-4-hydroxycoumarin compounds interact with DNA gyrase in a novel fashion. Proceedings of the Fourth Conference on DNA Topoisomerases in Therapy, abstract 22, p 29.
- 72 Kraulis, P. J. (1991). MOLSCRIPT — a program to produce both detailed and schematic plots of protein structures. J. Appl. Cryst. 24, 946–950.
- 73 Merritt, E. A. and Murphy, M. E. P. (1994). Raster3D version 2.0 — a program for photorealistic molecular graphics. Acta crystallogr. D50, 869–873.
