This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fournier, B.
Right arrow Articles by Hooper, D. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fournier, B.
Right arrow Articles by Hooper, D. C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 2000, p. 2160-2165, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Selective Targeting of Topoisomerase IV and DNA Gyrase in Staphylococcus aureus: Different Patterns of Quinolone- Induced Inhibition of DNA Synthesis

Bénédicte Fournier,1,dagger Xilin Zhao,2 Tao Lu,2 Karl Drlica,2 and David C. Hooper1,*

Infectious Disease Division and Medical Services, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-2696,1 and Public Health Research Institute, New York, New York 100162

Received 17 November 1999/Returned for modification 3 March 2000/Accepted 15 May 2000

The effect of quinolones on the inhibition of DNA synthesis in Staphylococcus aureus was examined by using single resistance mutations in parC or gyrA to distinguish action against gyrase or topoisomerase IV, respectively. Norfloxacin preferentially attacked topoisomerase IV and blocked DNA synthesis slowly, while nalidixic acid targeted gyrase and inhibited replication rapidly. Ciprofloxacin exhibited an intermediate response, consistent with both enzymes being targeted. The absence of RecA had little influence on target choice by this assay, indicating that differences in rebound (repair) DNA synthesis were not responsible for the results. At saturating drug concentrations, norfloxacin and a gyrA mutant were used to show that topoisomerase IV-norfloxacin-cleaved DNA complexes are distributed on the S. aureus chromosome at intervals of about 30 kbp. If cleaved complexes block DNA replication, as indicated by previous work, such close spacing of topoisomerase-quinolone-DNA complexes should block replication rapidly (replication forks are likely to encounter a cleaved complex within a minute). Thus, the slow inhibition of DNA synthesis at growth-inhibitory concentrations suggests that a subset of more distantly distributed complexes is physiologically relevant for drug action and is unlikely to be located immediately in front of the DNA replication fork.

* Corresponding author. Mailing address: Infectious Disease Division, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114-2696. Phone: (617) 726-3812. Fax: (617) 726-7416. E-mail: dhooper{at}partners.org.

dagger Present address: Unité de Biochimie Microbienne, Institut Pasteur, 75724 Paris Cedex 15, France.

Antimicrobial Agents and Chemotherapy, August 2000, p. 2160-2165, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Wirtz, C., Witte, W., Wolz, C., Goerke, C. (2009). Transcription of the phage-encoded Panton-Valentine leukocidin of Staphylococcus aureus is dependent on the phage life-cycle and on the host background. Microbiology 155: 3491-3499 [Abstract] [Full Text]  
  • Drlica, K., Malik, M., Kerns, R. J., Zhao, X. (2008). Quinolone-Mediated Bacterial Death. Antimicrob. Agents Chemother. 52: 385-392 [Full Text]  
  • Escudero, J. A., San Millan, A., Catalan, A., de la Campa, A. G., Rivero, E., Lopez, G., Dominguez, L., Moreno, M. A., Gonzalez-Zorn, B. (2007). First Characterization of Fluoroquinolone Resistance in Streptococcus suis. Antimicrob. Agents Chemother. 51: 777-782 [Abstract] [Full Text]  
  • Malik, M., Hussain, S., Drlica, K. (2007). Effect of Anaerobic Growth on Quinolone Lethality with Escherichia coli. Antimicrob. Agents Chemother. 51: 28-34 [Abstract] [Full Text]  
  • Truong-Bolduc, Q. C., Strahilevitz, J., Hooper, D. C. (2006). NorC, a New Efflux Pump Regulated by MgrA of Staphylococcus aureus. Antimicrob. Agents Chemother. 50: 1104-1107 [Abstract] [Full Text]  
  • Strahilevitz, J., Robicsek, A., Hooper, D. C. (2006). Role of the Extended {alpha}4 Domain of Staphylococcus aureus Gyrase A Protein in Determining Low Sensitivity to Quinolones. Antimicrob. Agents Chemother. 50: 600-606 [Abstract] [Full Text]  
  • Marrer, E., Satoh, A. T., Johnson, M. M., Piddock, L. J. V., Page, M. G. P. (2006). Global Transcriptome Analysis of the Responses of a Fluoroquinolone-Resistant Streptococcus pneumoniae Mutant and Its Parent to Ciprofloxacin. Antimicrob. Agents Chemother. 50: 269-278 [Abstract] [Full Text]  
  • Gruger, T., Nitiss, J. L., Maxwell, A., Zechiedrich, E. L., Heisig, P., Seeber, S., Pommier, Y., Strumberg, D. (2004). A Mutation in Escherichia coli DNA Gyrase Conferring Quinolone Resistance Results in Sensitivity to Drugs Targeting Eukaryotic Topoisomerase II. Antimicrob. Agents Chemother. 48: 4495-4504 [Abstract] [Full Text]  
  • Bisognano, C., Kelley, W. L., Estoppey, T., Francois, P., Schrenzel, J., Li, D., Lew, D. P., Hooper, D. C., Cheung, A. L., Vaudaux, P. (2004). A RecA-LexA-dependent Pathway Mediates Ciprofloxacin-induced Fibronectin Binding in Staphylococcus aureus. J. Biol. Chem. 279: 9064-9071 [Abstract] [Full Text]  
  • Pfeiffer, E. S., Hiasa, H. (2004). Replacement of ParC {alpha}4 Helix with That of GyrA Increases the Stability and Cytotoxicity of Topoisomerase IV-Quinolone-DNA Ternary Complexes. Antimicrob. Agents Chemother. 48: 608-611 [Abstract] [Full Text]  
  • Nilius, A. M., Shen, L. L., Hensey-Rudloff, D., Almer, L. S., Beyer, J. M., Balli, D. J., Cai, Y., Flamm, R. K. (2003). In Vitro Antibacterial Potency and Spectrum of ABT-492, a New Fluoroquinolone. Antimicrob. Agents Chemother. 47: 3260-3269 [Abstract] [Full Text]  
  • Sarda, L., Cremieux, A.-C., Lebellec, Y., Meulemans, A., Lebtahi, R., Hayem, G., Genin, R., Delahaye, N., Huten, D., Le Guludec, D. (2003). Inability of 99mTc-Ciprofloxacin Scintigraphy to Discriminate Between Septic and Sterile Osteoarticular Diseases. JNM 44: 920-926 [Abstract] [Full Text]  
  • Hiasa, H., Shea, M. E., Richardson, C. M., Gwynn, M. N. (2003). Staphylococcus aureus Gyrase-Quinolone-DNA Ternary Complexes Fail to Arrest Replication Fork Progression in Vitro. EFFECTS OF SALT ON THE DNA BINDING MODE AND THE CATALYTIC ACTIVITY OF S. AUREUS GYRASE. J. Biol. Chem. 278: 8861-8868 [Abstract] [Full Text]  
  • Sarda, L., Saleh-Mghir, A., Peker, C., Meulemans, A., Cremieux, A.-C., Le Guludec, D. (2002). Evaluation of 99mTc-Ciprofloxacin Scintigraphy in a Rabbit Model of Staphylococcus aureus Prosthetic Joint Infection. JNM 43: 239-245 [Abstract] [Full Text]  
  • Richardson, D. C., Bast, D., McGeer, A., Low, D. E. (2001). Evaluation of Susceptibility Testing To Detect Fluoroquinolone Resistance Mechanisms in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45: 1911-1914 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»