![]()
|
|
||||||||
J Biol Chem, Vol. 274, Issue 50, 35927-35932, December 10, 1999
§,
**
From the Departments of Quinolones are the most active oral
antibacterials in clinical use and act by increasing DNA cleavage
mediated by prokaryotic type II topoisomerases. Although topoisomerase
IV appears to be the primary cytotoxic target for most quinolones in
Gram-positive bacteria, interactions between the enzyme and these drugs
are poorly understood. Therefore, the effects of ciprofloxacin on the
DNA cleavage and religation reactions of Staphylococcus
aureus topoisomerase IV were characterized. Ciprofloxacin doubled
DNA scission at 150 nM drug and increased cleavage
~9-fold at 5 µM. Furthermore, it dramatically inhibited
rates of DNA religation mediated by S. aureus topoisomerase
IV. This inhibition of religation is in marked contrast to the effects
of antineoplastic quinolones on eukaryotic topoisomerase II, and
suggests that the mechanistic basis for quinolone action against type
II topoisomerases has not been maintained across evolutionary
boundaries. The apparent change in quinolone mechanism was not caused
by an overt difference in the drug interaction domain on
topoisomerase IV. Therefore, we propose that the mechanistic basis for
quinolone action is regulated by subtle changes in drug orientation
within the enzyme·drug·DNA ternary complex rather than gross
differences in the site of drug binding.
Biochemistry and
Medicine (Hematology/Oncology), Vanderbilt University School of
Medicine, Nashville, Tennessee 37232-0146 and the ¶ Department of
Cancer, Immunology, and Infectious Diseases, Pfizer Central Research,
Pfizer, Inc., Groton, Connecticut 06340
This article has been cited by other articles:
![]() |
K. Drlica, M. Malik, R. J. Kerns, and X. Zhao Quinolone-Mediated Bacterial Death Antimicrob. Agents Chemother., February 1, 2008; 52(2): 385 - 392. [Full Text] [PDF] |
||||
![]() |
M. Chatterji, S. Unniraman, S. Mahadevan, and V. Nagaraja Effect of different classes of inhibitors on DNA gyrase from Mycobacterium smegmatis J. Antimicrob. Chemother., October 1, 2001; 48(4): 479 - 485. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Roychoudhury, C. E. Catrenich, E. J. McIntosh, H. D. McKeever, K. M. Makin, P. M. Koenigs, and B. Ledoussal Quinolone Resistance in Staphylococci: Activities of New Nonfluorinated Quinolones against Molecular Targets in Whole Cells and Clinical Isolates Antimicrob. Agents Chemother., April 1, 2001; 45(4): 1115 - 1120. [Abstract] [Full Text] |
||||
![]() |
A. M. Wilstermann and N. Osheroff Positioning the 3'-DNA Terminus for Topoisomerase II-mediated Religation J. Biol. Chem., May 18, 2001; 276(21): 17727 - 17731. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |