Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1991 Feb;35(2):309–312. doi: 10.1128/aac.35.2.309

Significance of the methyl group on the oxazine ring of ofloxacin derivatives in the inhibition of bacterial and mammalian type II topoisomerases.

K Hoshino 1, K Sato 1, K Akahane 1, A Yoshida 1, I Hayakawa 1, M Sato 1, T Une 1, Y Osada 1
PMCID: PMC244997  PMID: 1850968

Abstract

A study was made of the correlation between the in vitro inhibitory effects of several quinolones, including four ofloxacin derivatives, on bacterial DNA gyrase from Escherichia coli KL-16 and on topoisomerase II from fetal calf thymus. No correlation was observed between the inhibitions of DNA gyrase activity and topoisomerase II activity. On the other hand, the inhibitory effects of these quinolones against topoisomerase II were closely correlated with their inhibition of cell growth. Furthermore, among the oxazine derivatives tested, the derivative with a methyl group at position 3 in an S configuration showed the highest activity against DNA gyrase and derivatives without a methyl group on the oxazine ring were more potent against topoisomerase II than those with a methyl group. Among these derivatives, DR-3355, the S isomer of ofloxacin, showed the highest activity against DNA gyrase and low activity against topoisomerase II. These results indicate that the methyl group on the oxazine ring plays an important role in the inhibitory activities of ofloxacin derivatives for these enzymes.

Full text

PDF
309

Selected References

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

  1. Bredberg A., Brant M., Riesbeck K., Azou Y., Forsgren A. 4-Quinolone antibiotics: positive genotoxic screening tests despite an apparent lack of mutation induction. Mutat Res. 1989 Mar;211(1):171–180. doi: 10.1016/0027-5107(89)90117-6. [DOI] [PubMed] [Google Scholar]
  2. Gellert M. DNA topoisomerases. Annu Rev Biochem. 1981;50:879–910. doi: 10.1146/annurev.bi.50.070181.004311. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Gellert M., Mizuuchi K., O'Dea M. H., Nash H. A. DNA gyrase: an enzyme that introduces superhelical turns into DNA. Proc Natl Acad Sci U S A. 1976 Nov;73(11):3872–3876. doi: 10.1073/pnas.73.11.3872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gerster J. F., Rohlfing S. R., Pecore S. E., Winandy R. M., Stern R. M., Landmesser J. E., Olsen R. A., Gleason W. B. Synthesis, absolute configuration, and antibacterial activity of 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H- benzo[ij]quinolizine-2-carboxylic acid. J Med Chem. 1987 May;30(5):839–843. doi: 10.1021/jm00388a016. [DOI] [PubMed] [Google Scholar]
  6. Halligan B. D., Edwards K. A., Liu L. F. Purification and characterization of a type II DNA topoisomerase from bovine calf thymus. J Biol Chem. 1985 Feb 25;260(4):2475–2482. [PubMed] [Google Scholar]
  7. Hayakawa I., Atarashi S., Yokohama S., Imamura M., Sakano K., Furukawa M. Synthesis and antibacterial activities of optically active ofloxacin. Antimicrob Agents Chemother. 1986 Jan;29(1):163–164. doi: 10.1128/aac.29.1.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Holden H. E., Barett J. F., Huntington C. M., Muehlbauer P. A., Wahrenburg M. G. Genetic profile of a nalidixic acid analog: a model for the mechanism of sister chromatid exchange induction. Environ Mol Mutagen. 1989;13(3):238–252. doi: 10.1002/em.2850130308. [DOI] [PubMed] [Google Scholar]
  9. Hooper D. C., Wolfson J. S. Mode of action of the quinolone antimicrobial agents: review of recent information. Rev Infect Dis. 1989 Jul-Aug;11 (Suppl 5):S902–S911. doi: 10.1093/clinids/11.supplement_5.s902. [DOI] [PubMed] [Google Scholar]
  10. Hoshino K., Sato K., Une T., Osada Y. Inhibitory effects of quinolones on DNA gyrase of Escherichia coli and topoisomerase II of fetal calf thymus. Antimicrob Agents Chemother. 1989 Oct;33(10):1816–1818. doi: 10.1128/aac.33.10.1816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hussy P., Maass G., Tümmler B., Grosse F., Schomburg U. Effect of 4-quinolones and novobiocin on calf thymus DNA polymerase alpha primase complex, topoisomerases I and II, and growth of mammalian lymphoblasts. Antimicrob Agents Chemother. 1986 Jun;29(6):1073–1078. doi: 10.1128/aac.29.6.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Oomori Y., Yasue T., Aoyama H., Hirai K., Suzue S., Yokota T. Effects of fleroxacin on HeLa cell functions and topoisomerase II. J Antimicrob Chemother. 1988 Oct;22 (Suppl 500):91–97. doi: 10.1093/jac/22.supplement_d.91. [DOI] [PubMed] [Google Scholar]
  13. Pessina A., Neri M. G., Muschiato A., Mineo E., Cocuzza G. Effect of fluoroquinolones on the in-vitro proliferation of myeloid precursor cells. J Antimicrob Chemother. 1989 Aug;24(2):203–208. doi: 10.1093/jac/24.2.203. [DOI] [PubMed] [Google Scholar]
  14. Sato K., Matsuura Y., Inoue M., Une T., Osada Y., Ogawa H., Mitsuhashi S. In vitro and in vivo activity of DL-8280, a new oxazine derivative. Antimicrob Agents Chemother. 1982 Oct;22(4):548–553. doi: 10.1128/aac.22.4.548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Shen L. L., Baranowski J., Pernet A. G. Mechanism of inhibition of DNA gyrase by quinolone antibacterials: specificity and cooperativity of drug binding to DNA. Biochemistry. 1989 May 2;28(9):3879–3885. doi: 10.1021/bi00435a038. [DOI] [PubMed] [Google Scholar]
  16. Shen L. L., Mitscher L. A., Sharma P. N., O'Donnell T. J., Chu D. W., Cooper C. S., Rosen T., Pernet A. G. Mechanism of inhibition of DNA gyrase by quinolone antibacterials: a cooperative drug--DNA binding model. Biochemistry. 1989 May 2;28(9):3886–3894. doi: 10.1021/bi00435a039. [DOI] [PubMed] [Google Scholar]
  17. Shen L. L., Pernet A. G. Mechanism of inhibition of DNA gyrase by analogues of nalidixic acid: the target of the drugs is DNA. Proc Natl Acad Sci U S A. 1985 Jan;82(2):307–311. doi: 10.1073/pnas.82.2.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Somekh E., Douer D., Shaked N., Rubinstein E. In vitro effects of ciprofloxacin and pefloxacin on growth of normal human hematopoietic progenitor cells and on leukemic cell lines. J Pharmacol Exp Ther. 1989 Jan;248(1):415–418. [PubMed] [Google Scholar]
  19. Somekh E., Lev B., Schwartz E., Barzilai A., Rubinstein E. The effect of ciprofloxacin and pefloxacin on bone marrow engraftment in the spleen of mice. J Antimicrob Chemother. 1989 Feb;23(2):247–251. doi: 10.1093/jac/23.2.247. [DOI] [PubMed] [Google Scholar]
  20. Une T., Fujimoto T., Sato K., Osada Y. In vitro activity of DR-3355, an optically active ofloxacin. Antimicrob Agents Chemother. 1988 Sep;32(9):1336–1340. doi: 10.1128/aac.32.9.1336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Wentland M. P., Perni R. B., Dorff P. H., Rake J. B. Synthesis and bacterial DNA gyrase inhibitory properties of a spirocyclopropylquinolone derivative. J Med Chem. 1988 Sep;31(9):1694–1697. doi: 10.1021/jm00117a005. [DOI] [PubMed] [Google Scholar]
  22. Worton R. G., McCulloch E. A., Till J. E. Physical separation of hemopoietic stem cells from cells forming colonies in culture. J Cell Physiol. 1969 Oct;74(2):171–182. doi: 10.1002/jcp.1040740209. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES