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, December 2000, p. 3344-3350, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mechanisms and Frequency of Resistance to Premafloxacin in Staphylococcus aureus: Novel Mutations Suggest Novel Drug-Target Interactions

Dilek Ince and David C. Hooper*

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

Received 21 April 2000/Returned for modification 27 June 2000/Accepted 11 September 2000

Premafloxacin is a novel 8-methoxy fluoroquinolone with enhanced activity against Staphylococcus aureus. We found premafloxacin to be 32-fold more active than ciprofloxacin against wild-type S. aureus. Single mutations in either subunit of topoisomerase IV caused a four- to eightfold increase in the MICs of both quinolones. A double mutation (gyrA and either grlA or grlB) caused a 32-fold increase in the MIC of premafloxacin, while the MIC of ciprofloxacin increased 128-fold. Premafloxacin appeared to be a poor substrate for NorA, with NorA overexpression causing an increase of twofold or less in the MIC of premafloxacin in comparison to a fourfold increase in the MIC of ciprofloxacin. The frequency of selection of resistant mutants was 6.4 × 10-10 to 4.0 × 10-7 at twofold the MIC of premafloxacin, 2 to 4 log10 less than that with ciprofloxacin. Single-step mutants could not be selected at higher concentrations of premafloxacin. In five single-step mutants, only one previously described uncommon mutation (Ala116Glu), and four novel mutations (Arg43Cys, Asp69Tyr, Ala176Thr, and Pro157Leu), three of which were outside the quinolone resistance-determining region (QRDR) were found. Genetic linkage studies, in which incross of grlA+ and outcross of mutations were performed, showed a high correlation between the mutations and the resistance phenotypes, and allelic exchange experiments confirmed the role of the novel mutations in grlA in resistance. Our results suggest that although topoisomerase IV is the primary target of premafloxacin, premafloxacin appears to interact with topoisomerase IV in a manner different from that of other quinolones and that the range of the QRDR of grlA should be expanded.

* 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.

Antimicrobial Agents and Chemotherapy, December 2000, p. 3344-3350, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Beeton, M. L., Chalker, V. J., Maxwell, N. C., Kotecha, S., Spiller, O. B. (2009). Concurrent Titration and Determination of Antibiotic Resistance in Ureaplasma Species with Identification of Novel Point Mutations in Genes Associated with Resistance. Antimicrob. Agents Chemother. 53: 2020-2027 [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]  
  • Butler, M. M., LaMarr, W. A., Foster, K. A., Barnes, M. H., Skow, D. J., Lyden, P. T., Kustigian, L. M., Zhi, C., Brown, N. C., Wright, G. E., Bowlin, T. L. (2007). Antibacterial Activity and Mechanism of Action of a Novel Anilinouracil-Fluoroquinolone Hybrid Compound. Antimicrob. Agents Chemother. 51: 119-127 [Abstract] [Full Text]  
  • Bhagwat, S. S., Mundkur, L. A., Gupte, S. V., Patel, M. V., Khorakiwala, H. F. (2006). The Anti-Methicillin-Resistant Staphylococcus aureus Quinolone WCK 771 Has Potent Activity against Sequentially Selected Mutants, Has a Narrow Mutant Selection Window against Quinolone-Resistant Staphylococcus aureus, and Preferentially Targets DNA Gyrase . Antimicrob. Agents Chemother. 50: 3568-3579 [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]  
  • 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]  
  • Ahmed, A. M, Miyoshi, S.-i., Shinoda, S., Shimamoto, T. (2005). Molecular characterization of a multidrug-resistant strain of enteroinvasive Escherichia coli O164 isolated in Japan. J Med Microbiol 54: 273-278 [Abstract] [Full Text]  
  • Campion, J. J., McNamara, P. J., Evans, M. E. (2004). Evolution of Ciprofloxacin-Resistant Staphylococcus aureus in In Vitro Pharmacokinetic Environments. Antimicrob. Agents Chemother. 48: 4733-4744 [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]  
  • Bebear, C. M., Renaudin, H., Charron, A., Clerc, M., Pereyre, S., Bebear, C. (2003). DNA Gyrase and Topoisomerase IV Mutations in Clinical Isolates of Ureaplasma spp. and Mycoplasma hominis Resistant to Fluoroquinolones. Antimicrob. Agents Chemother. 47: 3323-3325 [Abstract] [Full Text]  
  • Macinga, D. R., Renick, P. J., Makin, K. M., Ellis, D. H., Kreiner, A. A., Li, M., Rupnik, K. J., Kincaid, E. M., Wallace, C. D., Ledoussal, B., Morris, T. W. (2003). Unique Biological Properties and Molecular Mechanism of 5,6-Bridged Quinolones. Antimicrob. Agents Chemother. 47: 2526-2537 [Abstract] [Full Text]  
  • Ince, D., Zhang, X., Hooper, D. C. (2003). Activity of and Resistance to Moxifloxacin in Staphylococcus aureus. Antimicrob. Agents Chemother. 47: 1410-1415 [Abstract] [Full Text]  
  • Ince, D., Zhang, X., Silver, L. C., Hooper, D. C. (2003). Topoisomerase Targeting with and Resistance to Gemifloxacin in Staphylococcus aureus. Antimicrob. Agents Chemother. 47: 274-282 [Abstract] [Full Text]  
  • Butler, M. M., Skow, D. J., Stephenson, R. O., Lyden, P. T., LaMarr, W. A., Foster, K. A. (2002). Low Frequencies of Resistance among Staphylococcus and Enterococcus Species to the Bactericidal DNA Polymerase Inhibitor N3-Hydroxybutyl 6-(3'-Ethyl-4'-Methylanilino) Uracil. Antimicrob. Agents Chemother. 46: 3770-3775 [Abstract] [Full Text]  
  • Kaatz, G. W., Moudgal, V. V., Seo, S. M. (2002). Identification and characterization of a novel efflux-related multidrug resistance phenotype in Staphylococcus aureus. J Antimicrob Chemother 50: 833-838 [Abstract] [Full Text]  
  • Ince, D., Zhang, X., Silver, L. C., Hooper, D. C. (2002). Dual Targeting of DNA Gyrase and Topoisomerase IV: Target Interactions of Garenoxacin (BMS-284756, T-3811ME), a New Desfluoroquinolone. Antimicrob. Agents Chemother. 46: 3370-3380 [Abstract] [Full Text]  
  • Hannachi-M'Zali, F., Ambler, J. E., Taylor, C. F., Hawkey, P. M. (2002). Examination of single and multiple mutations involved in resistance to quinolones in Staphylococcus aureus by a combination of PCR and denaturing high-performance liquid chromatography (DHPLC). J Antimicrob Chemother 50: 649-655 [Abstract] [Full Text]  
  • Pan, X.-S., Hamlyn, P. J., Talens-Visconti, R., Alovero, F. L., Manzo, R. H., Fisher, L. M. (2002). Small-Colony Mutants of Staphylococcus aureus Allow Selection of Gyrase-Mediated Resistance to Dual-Target Fluoroquinolones. Antimicrob. Agents Chemother. 46: 2498-2506 [Abstract] [Full Text]  
  • Valdezate, S., Vindel, A., Echeita, A., Baquero, F., Canto, R. (2002). Topoisomerase II and IV Quinolone Resistance-Determining Regions in Stenotrophomonas maltophilia Clinical Isolates with Different Levels of Quinolone Susceptibility. Antimicrob. Agents Chemother. 46: 665-671 [Abstract] [Full Text]  
  • Roychoudhury, S., Twinem, T. L., Makin, K. M., Nienaber, M. A., Li, C., Morris, T. W., Ledoussal, B., Catrenich, C. E. (2001). Staphylococcus aureus Mutants Isolated via Exposure to Nonfluorinated Quinolones: Detection of Known and Unique Mutations. Antimicrob. Agents Chemother. 45: 3422-3426 [Abstract] [Full Text]  
  • Weigel, L. M., Anderson, G. J., Facklam, R. R., Tenover, F. C. (2001). Genetic Analyses of Mutations Contributing to Fluoroquinolone Resistance in Clinical Isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45: 3517-3523 [Abstract] [Full Text]  
  • Pan, X.-S., Yague, G., Fisher, L. M. (2001). Quinolone Resistance Mutations in Streptococcus pneumoniae GyrA and ParC Proteins: Mechanistic Insights into Quinolone Action from Enzymatic Analysis, Intracellular Levels, and Phenotypes of Wild-Type and Mutant Proteins. Antimicrob. Agents Chemother. 45: 3140-3147 [Abstract] [Full Text]  
  • Discotto, L. F., Lawrence, L. E., Denbleyker, K. L., Barrett, J. F. (2001). Staphylococcus aureus Mutants Selected by BMS-284756. Antimicrob. Agents Chemother. 45: 3273-3275 [Abstract] [Full Text]  
  • Lu, T., Zhao, X., Li, X., Drlica-Wagner, A., Wang, J.-Y., Domagala, J., Drlica, K. (2001). Enhancement of Fluoroquinolone Activity by C-8 Halogen and Methoxy Moieties: Action against a Gyrase Resistance Mutant of Mycobacterium smegmatis and a Gyrase-Topoisomerase IV Double Mutant of Staphylococcus aureus. Antimicrob. Agents Chemother. 45: 2703-2709 [Abstract] [Full Text]  
  • Ince, D., Hooper, D. C. (2001). Mechanisms and Frequency of Resistance to Gatifloxacin in Comparison to AM-1121 and Ciprofloxacin in Staphylococcus aureus. Antimicrob. Agents Chemother. 45: 2755-2764 [Abstract] [Full Text]  
  • Friedman, S. M., Lu, T., Drlica, K. (2001). Mutation in the DNA Gyrase A Gene of Escherichia coli That Expands the Quinolone Resistance-Determining Region. Antimicrob. Agents Chemother. 45: 2378-2380 [Abstract] [Full Text]  
  • Fukuda, H., Kishii, R., Takei, M., Hosaka, M. (2001). Contributions of the 8-Methoxy Group of Gatifloxacin to Resistance Selectivity, Target Preference, and Antibacterial Activity against Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45: 1649-1653 [Abstract] [Full Text]  
  • Linde, H.-J., Schmidt, M., Fuchs, E., Reischl, U., Niller, H.-H., Lehn, N. (2001). In Vitro Activities of Six Quinolones and Mechanisms of Resistance in Staphylococcus aureus and Coagulase-Negative Staphylococci. Antimicrob. Agents Chemother. 45: 1553-1557 [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»