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 Ince, D.
Right arrow Articles by Hooper, D. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ince, D.
Right arrow Articles by Hooper, D. C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, January 2003, p. 274-282, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.274-282.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Topoisomerase Targeting with and Resistance to Gemifloxacin in Staphylococcus aureus

Dilek Ince, Xiamei Zhang, L. Christine Silver, and David C. Hooper*

Division of Infectious Diseases and Medical Services, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-2696

Received 13 August 2002/ Returned for modification 24 September 2002/ Accepted 24 October 2002

Gemifloxacin, a novel quinolone with potent activity against Staphylococcus aureus, was 8- to 16-fold more active against wild-type S. aureus than ciprofloxacin. The two- to fourfold increase in the MIC of gemifloxacin in genetically defined grlBA mutants and the twofold increase in a single gyrA mutant, supported by the low frequency of selection of resistant mutants at twice the MIC (7.4 x 10-11 to 1.1 x 10-10), suggested similar targeting of the two enzymes by gemifloxacin. Dual mutations in both gyrase and topoisomerase IV caused a 64- to 128-fold increase in the MIC of gemifloxacin, similar to that seen with ciprofloxacin. Gemifloxacin also had similar activity in vitro against topoisomerase IV and gyrase purified from S. aureus (50% inhibitory concentrations of 0.25 and 0.31 µg/ml, respectively). This activity was 10- to 20-fold higher than that of ciprofloxacin for topoisomerase IV and 33-fold higher than that for gyrase. In contrast to the in vitro findings, only topoisomerase IV mutants were selected in first-step mutants. Overexpression of the NorA efflux pump had a minimal effect on resistance to gemifloxacin, and a mutation in the promoter region of the gene for NorA was selected only in the sixth step of serial selection of mutants. Our data show that although gemifloxacin targets purified topoisomerase IV and gyrase similarly in vitro, topoisomerase IV is the preferred target in the bacteria. Selection of novel resistance mutations in grlA requires further expansion of quinolone-resistance-determining regions, and their study may provide increased insight into enzyme-quinolone interactions.

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

Antimicrobial Agents and Chemotherapy, January 2003, p. 274-282, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.274-282.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cambau, E., Matrat, S., Pan, X.-S., Roth Dit Bettoni, R., Corbel, C., Aubry, A., Lascols, C., Driot, J.-Y., Fisher, L. M. (2009). Target specificity of the new fluoroquinolone besifloxacin in Streptococcus pneumoniae, Staphylococcus aureus and Escherichia coli. J Antimicrob Chemother 63: 443-450 [Abstract] [Full Text]  
  • Black, M. T., Stachyra, T., Platel, D., Girard, A.-M., Claudon, M., Bruneau, J.-M., Miossec, C. (2008). Mechanism of Action of the Antibiotic NXL101, a Novel Nonfluoroquinolone Inhibitor of Bacterial Type II Topoisomerases. Antimicrob. Agents Chemother. 52: 3339-3349 [Abstract] [Full Text]  
  • Cheng, J., Thanassi, J. A., Thoma, C. L., Bradbury, B. J., Deshpande, M., Pucci, M. J. (2007). Dual Targeting of DNA Gyrase and Topoisomerase IV: Target Interactions of Heteroaryl Isothiazolones in Staphylococcus aureus. Antimicrob. Agents Chemother. 51: 2445-2453 [Abstract] [Full Text]  
  • Grossman, T. H., Bartels, D. J., Mullin, S., Gross, C. H., Parsons, J. D., Liao, Y., Grillot, A.-L., Stamos, D., Olson, E. R., Charifson, P. S., Mani, N. (2007). Dual Targeting of GyrB and ParE by a Novel Aminobenzimidazole Class of Antibacterial Compounds. Antimicrob. Agents Chemother. 51: 657-666 [Abstract] [Full Text]  
  • Riordan, J. T., Muthaiyan, A., Van Voorhies, W., Price, C. T., Graham, J. E., Wilkinson, B. J., Gustafson, J. E. (2007). Response of Staphylococcus aureus to Salicylate Challenge. J. Bacteriol. 189: 220-227 [Abstract] [Full Text]  
  • Strahilevitz, J., Truong-Bolduc, Q. C., Hooper, D. C. (2005). DX-619, a Novel Des-Fluoro(6) Quinolone Manifesting Low Frequency of Selection of Resistant Staphylococcus aureus Mutants: Quinolone Resistance beyond Modification of Type II Topoisomerases. Antimicrob. Agents Chemother. 49: 5051-5057 [Abstract] [Full Text]  
  • Poole, K. (2005). Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 56: 20-51 [Abstract] [Full Text]  
  • Korzheva, N., Davies, T. A., Goldschmidt, R. (2005). Novel Ser79Leu and Ser81Ile Substitutions in the Quinolone Resistance-Determining Regions of ParC Topoisomerase IV and GyrA DNA Gyrase Subunits from Recent Fluoroquinolone-Resistant Streptococcus pneumoniae Clinical Isolates. Antimicrob. Agents Chemother. 49: 2479-2486 [Abstract] [Full Text]  
  • Strahilevitz, J., Hooper, D. C. (2005). Dual Targeting of Topoisomerase IV and Gyrase To Reduce Mutant Selection: Direct Testing of the Paradigm by Using WCK-1734, a New Fluoroquinolone, and Ciprofloxacin. Antimicrob. Agents Chemother. 49: 1949-1956 [Abstract] [Full Text]  
  • Patel, M. V., De Souza, N. J., Gupte, S. V., Jafri, M. A., Bhagwat, S. S., Chugh, Y., Khorakiwala, H. F., Jacobs, M. R., Appelbaum, P. C. (2004). Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models. Antimicrob. Agents Chemother. 48: 4754-4761 [Abstract] [Full Text]  
  • Yoo, B. K, Triller, D. M, Yong, C.-S., Lodise, T. P (2004). Gemifloxacin: A New Fluoroquinolone Approved for Treatment of Respiratory Infections. The Annals of Pharmacotherapy 38: 1226-1235 [Abstract] [Full Text]  
  • Ince, D., Hooper, D. C. (2003). Quinolone Resistance Due to Reduced Target Enzyme Expression. J. Bacteriol. 185: 6883-6892 [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»