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A Comparison of Active Site Binding of 4-Quinolones and Novel Flavone Gyrase Inhibitors to DNA Gyrase

  • J. J. Hilliard
  • H. M. Krause
  • J. I. Bernstein
  • J. A. Fernandez
  • V. Nguyen
  • K. A. Ohemeng
  • J. F. Barrett
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 390)

Abstract

4-Quinolone antibacterials are known to inhibit the topoisomerase II (DNA gyrase) of numerous bacterial species (among them Escherichia coli, Micrococcus luteus, Mycobacterium species, Pseudomonas aeruginosa, and Staphylococcus aureus), although to differing degrees of potency1,2,3 Optimal potency is based on the balance in structure-activity relationship between the permeability of the agent through the bacterial cell wall and membrane(s), and activity at the enzyme level.1,3 Activity is based on the observations that 4-quinolone antibacterials target the Gyr A subunit of the DNA gyrase holoenzyme,4 inhibiting supercoiling and facilitating the “cleavable complex” by inhibiting the religation of DNA gyrase holoenzymemediated sequence-specific 4-base pair staggered cuts on the DNA duplex.5 Such inhibition can be observed and quantitated by running either the in vitro DNA gyrase supercoiling inhibition assay or the “cleavable complex” DNA gyrase assay.6,7

Keywords

Nalidixic Acid Ellagic Acid Micrococcus Luteus Cleavable Complex Pipemidic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    J.H. Paton and D.S. Reeves. 1988. Fluoroquinolone antibiotics. Microbiology, pharmocokinetics and clinical use. Drugs 36: 193–228.Google Scholar
  2. 2.
    Y.X. Furet and J.C. Pechere. 1991. Newly documented antimicrobial activity of quinolones. Eur. J. Clin. Microbial. Infect. Dis. 10: 249–254.Google Scholar
  3. 3.
    H.C. Neu. 1992. Quinolone antimicrobial agents. Annual Rev. Med. 43: 465–486.Google Scholar
  4. 4.
    A. Maxwell. 1992. The molecular basis of quinolone action. J. Antimicrob. Chemotherapy 30: 409–414.Google Scholar
  5. 5.
    A. Morrison and N.R. Cozzarelli. 1979. Site-specific cleavage of DNA by E. coli DNA gyrase. Cell 17: 175–184.PubMedCrossRefGoogle Scholar
  6. 6.
    J.M. Domagala, L.D. Hanna, C.L. Heifetz, M.P. Hutt, T.F. Mich, J.P. Sanchez, and M. Solomon. 1986. New structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay. J. Med. Chem. 29: 394–404.Google Scholar
  7. 7.
    J.F. Barrett, T.D. Gootz, P.R. McGuirk, C.A. Farrell, and S.A. Sokolowski. 1989. Use of in vitro topoisomerase II assays for studying quinolone antibacterial agents A timicrob. Agents Chemother. 33: 1697–1703.CrossRefGoogle Scholar
  8. 8.
    G-Later. 1989. Ciprofloxacin: toxicologic evaluation of additional safety data. The Am. J. of Medicine 82 (Suppl 4A): 91–93.Google Scholar
  9. d. K. Akahane, M.A. Sekiguchi, T. Une and Y. Osada. 1989. Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gammaaminobutyric acid receptor sites. Antimicrob Agents Chemother. 33: 1704–1708.PubMedCrossRefGoogle Scholar
  10. 10.
    S.P. Sachchar, N.N. Tripathi, and A.K. Singh. 1987. Synthesis of fluorinated heteroaryl flavenoids their biological activity. Ind. J. Chem. 26B: 493–495.Google Scholar
  11. 11.
    M. Weidenborner, H. Hindorf, H.C. Jha, and P. Tsotsonos. 1990. Antifungal activity of flavonoids against storage fungi of the genus spergillus. Phytochem. 29: 1103–1105.CrossRefGoogle Scholar
  12. 12.
    K.A. Ohemeng, C.F. Schwender, K.P. Fu, and J.F. Barrett. 1993. DNA gyrase inhibitory and antibacterial activity of some flavones. Bioorganic Medicinal Chem. Letters 3 (2): 225–230.CrossRefGoogle Scholar
  13. 13.
    L.L. Shen and A.G. Pernet. 1985. Mechanism of inhibition of DNA gyrase by analogues of nalidixic acid: the target of the drugs is DNA. Proc. Natl. Acad. Sci. USA 82: 307–311.Google Scholar
  14. 14.
    L.L. Shen, J. Baranowski, and A.G. Pernet. 1989. Mechanism of inhibition of DNA gyrase by quinolone antibacterials: specificity and cooperatively of drug binding to DNA. Biochemistry 28: 3879–3885.PubMedCrossRefGoogle Scholar
  15. 15.
    K.M. Mizuuchi, H. O ‘Dea, and M. Gellert. 1978. DNA gyrase: subunit structure and ATPase activity of the purified enzyme. Proc. Natl. Acad. Sci. USA 75: 5960–5963.Google Scholar
  16. 16.
    J.F. Barrett, J.I. Bernstein, H.M. Krause, J.J. Hilliard, and K.A. Ohemeng. 1993. Testing potential gyrase inhibitors of bacterial DNA gyrase: a comparison of the supercoiling inhibition assay and “cleavable complex” assay. Anal. Biochem. 214: 313–317.Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • J. J. Hilliard
    • 1
  • H. M. Krause
    • 1
  • J. I. Bernstein
    • 1
  • J. A. Fernandez
    • 1
  • V. Nguyen
    • 1
  • K. A. Ohemeng
    • 1
  • J. F. Barrett
    • 1
  1. 1.The R. W. Johnson Pharmaceutical Research InstituteRaritanUSA

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