The Interaction of Drugs with DNA Gyrase: A Model for the Molecular Basis of Quinolone Action

Abstract DNA gyrase supercoils DNA in bacteria. The fact that it is essential in all bacteria and absent from eukaryotes makes it an ideal drug target. We discuss the action of coumarin and quinolone drugs on gyrase. In the case of coumarins, the drugs are known to be competitive inhibitors of the gyrase ATPase reaction. From a combination of structural and biochemical studies, the molecular details of the gyrase-coumarin complex are well established. In the case of quinolones, the drugs are thought to act by stabilising a cleavage complex between gyrase and DNA that arrests polymerases in vivo. The exact nature of the gyrase-quinolone-DNA complex is not known; we propose a model for this complex based on structural and biochemical data.

[1]  Fritz Eckstein,et al.  Nucleic acids and molecular biology , 1987 .

[2]  G. Orphanides,et al.  The interaction of coumarin antibiotics with fragments of DNA gyrase B protein. , 1996, Biochemistry.

[3]  A. Maxwell,et al.  gyrB mutations which confer coumarin resistance also affect DNA supercoiling and ATP hydrolysis by Escherichia coli DNA gyrase , 1992, Molecular Microbiology.

[4]  Anthony Maxwell,et al.  Crystal structure of the breakage–reunion domain of DNA gyrase , 1997, Nature.

[5]  N. Cozzarelli,et al.  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. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[6]  H. Ito,et al.  Mechanism of action of quinolones against Escherichia coli DNA gyrase , 1993, Antimicrobial Agents and Chemotherapy.

[7]  M. Gellert,et al.  Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Roca,et al.  DNA transport by a type II DNA topoisomerase: Evidence in favor of a two-gate mechanism , 1994, Cell.

[9]  B. Gatto,et al.  On the mechanism of action of quinolone drugs. , 1993, Trends in microbiology.

[10]  B. Gatto,et al.  Quinolone binding to DNA is mediated by magnesium ions. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. Maxwell.  DNA gyrase as a drug target. , 1997, Trends in microbiology.

[12]  A. Maxwell,et al.  The DNA Gyrase-Quinolone Complex , 1998, The Journal of Biological Chemistry.

[13]  A. Maxwell,et al.  A single point mutation in the DNA gyrase A protein greatly reduces binding of fluoroquinolones to the gyrase-DNA complex , 1993, Antimicrobial Agents and Chemotherapy.

[14]  S. W. Matson,et al.  Disruption of a topoisomerase-DNA cleavage complex by a DNA helicase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Crouzet,et al.  Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones , 1994, Molecular microbiology.

[16]  A. Khodursky,et al.  Topoisomerase IV is a target of quinolones in Escherichia coli. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Walter H.J. Ward,et al.  The entropic penalty of ordered water accounts for weaker binding of the antibiotic novobiocin to a resistant mutant of DNA gyrase: a thermodynamic and crystallographic study. , 1997, Biochemistry.

[18]  K. Kreuzer,et al.  Localization of an aminoacridine antitumor agent in a type II topoisomerase-DNA complex. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[19]  L. Piddock,et al.  Mechanisms of Resistance to Fluoroquinolones , 1998 .

[20]  W. Goss,et al.  Mechanism of Action of Nalidixic Acid on Escherichia coli II. Inhibition of Deoxyribonucleic Acid Synthesis , 1965, Journal of bacteriology.

[21]  A. Maxwell,et al.  Locking the DNA gate of DNA gyrase: investigating the effects on DNA cleavage and ATP hydrolysis. , 1999, Biochemistry.

[22]  H. Hiasa,et al.  Interactions between DNA Helicases and Frozen Topoisomerase IV-Quinolone-DNA Ternary Complexes* , 1999, The Journal of Biological Chemistry.

[23]  D. Wigley,et al.  Crystal structure of an N-terminal fragment of the DNA gyrase B protein , 1991, Nature.

[24]  L. Hurley,et al.  Self-assembly of a quinobenzoxazine-Mg2+ complex on DNA: a new paradigm for the structure of a drug-DNA complex and implications for the structure of the quinolone bacterial gyrase-DNA complex. , 1995, Journal of medicinal chemistry.

[25]  K. Kreuzer,et al.  Mutational analysis of a type II topoisomerase cleavage site: distinct requirements for enzyme and inhibitors. , 1993, The EMBO journal.

[26]  S. Tornaletti,et al.  Studies on the interaction of 4-quinolones with DNA by DNA unwinding experiments. , 1988, Biochimica et biophysica acta.

[27]  J. Berger,et al.  Structure and mechanism of DNA topoisomerase II , 1996, Nature.

[28]  A. Maxwell,et al.  The 24 kDa N‐terminal sub‐domain of the DNA gyrase B protein binds coumarin drugs , 1994, Molecular microbiology.

[29]  A. Maxwell,et al.  DNA cleavage is not required for the binding of quinolone drugs to the DNA gyrase-DNA complex. , 1996, Biochemistry.

[30]  A. Maxwell,et al.  Probing the two-gate mechanism of DNA gyrase using cysteine cross-linking. , 1999, Biochemistry.

[31]  J. Pouliot,et al.  Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. , 1999, Science.

[32]  P. Brown,et al.  Energy coupling in DNA gyrase and the mechanism of action of novobiocin. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[33]  J. Wang,et al.  Similarity in the catalysis of DNA breakage and rejoining by type IA and IIA DNA topoisomerases. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  D. Wigley.  Structure and Mechanism of DNA Gyrase , 1995 .

[35]  H. Hiasa,et al.  Two Distinct Modes of Strand Unlinking during θ-Type DNA Replication* , 1996, The Journal of Biological Chemistry.

[36]  W. Kohlbrenner,et al.  Mechanism of quinolone inhibition of DNA gyrase. Appearance of unique norfloxacin binding sites in enzyme-DNA complexes. , 1989, The Journal of biological chemistry.

[37]  S. Nakamura,et al.  Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli , 1990, Antimicrobial Agents and Chemotherapy.

[38]  M. Inoue,et al.  Alterations in the DNA topoisomerase IV grlA gene responsible for quinolone resistance in Staphylococcus aureus , 1996, Antimicrobial agents and chemotherapy.

[39]  A. Maxwell,et al.  Conformational Changes in DNA Gyrase Revealed by Limited Proteolysis* , 1998, The Journal of Biological Chemistry.

[40]  J. Crouzet,et al.  Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus , 1995, Antimicrobial agents and chemotherapy.

[41]  I. Eperon,et al.  The complex of DNA gyrase and quinolone drugs with DNA forms a barrier to transcription by RNA polymerase. , 1994, Journal of molecular biology.

[42]  J. Roca,et al.  The capture of a DNA double helix by an ATP-dependent protein clamp: A key step in DNA transport by type II DNA topoisomerases , 1992, Cell.

[43]  N. Osheroff,et al.  Topoisomerase Poisons: Harnessing the Dark Side of Enzyme Mechanism (*) , 1995, The Journal of Biological Chemistry.

[44]  A. Breeze,et al.  The high‐resolution crystal structure of a 24‐kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin , 1997, Proteins.

[45]  J. Domagala,et al.  New structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay. , 1986, Journal of medicinal chemistry.

[46]  I. del Castillo,et al.  An unusual mechanism for resistance to the antibiotic coumermycin A1. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[47]  S. Inoue,et al.  New nalidixic acid resistance mutations related to deoxyribonucleic acid gyrase activity , 1981, Journal of bacteriology.

[48]  N. Cozzarelli,et al.  Escherichia coli Mutants Thermosensitive for Deoxyribonucleic Acid Gyrase Subunit A: Effects on Deoxyribonucleic Acid Replication, Transcription, and Bacteriophage Growth , 1979, Journal of bacteriology.

[49]  K. Drlica,et al.  DNA gyrase, topoisomerase IV, and the 4-quinolones , 1997, Microbiology and molecular biology reviews : MMBR.

[50]  A. Burgin,et al.  A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[51]  L. Elwell,et al.  In vitro cleavable-complex assay to monitor antimicrobial potency of quinolones , 1988, Antimicrobial Agents and Chemotherapy.

[52]  W. Goss,et al.  Mechanism of Action of Nalidixic Acid on Escherichia coli III. Conditions Required for Lethality , 1966, Journal of bacteriology.

[53]  C V Smith,et al.  The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X‐ray crystallography. , 1996, The EMBO journal.

[54]  R. J. Reece,et al.  DNA gyrase: structure and function. , 1991, Critical reviews in biochemistry and molecular biology.

[55]  G. Orphanides,et al.  Probing the binding of coumarins and cyclothialidines to DNA gyrase. , 1999, Biochemistry.

[56]  A. Pernet,et al.  Mechanism of inhibition of DNA gyrase by analogues of nalidixic acid: the target of the drugs is DNA. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Deborah Fass,et al.  Quaternary changes in topoisomerase II may direct orthogonal movement of two DNA strands , 1999, Nature Structural Biology.