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Gene Review

gamma  -  topoisomerase

Streptococcus pyogenes

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Disease relevance of gamma


High impact information on gamma

  • We investigated DNA cleavage by Streptococcus pneumoniae topo IV and gyrase stabilized by gemifloxacin and other antipneumococcal fluoroquinolones [1].
  • The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors [5].
  • In Vitro and In Vivo Activities of PD 0305970 and PD 0326448, New Bacterial Gyrase/Topoisomerase Inhibitors with Potent Antibacterial Activities versus Multidrug-Resistant Gram-Positive and Fastidious Organism Groups [6].
  • A structure-guided drug design approach was used to optimize a novel series of aminobenzimidazoles that inhibit the essential ATPase activities of bacterial DNA gyrase and topoisomerase IV and that show potent activities against a variety of bacterial pathogens [7].
  • Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics [8].

Chemical compound and disease context of gamma


Biological context of gamma


Anatomical context of gamma

  • Changes in pneumococcal cell wall penicillin-binding proteins account for resistance to penicillins, mutations in the ermB gene cause high-level macrolide resistance and mutations in topoisomerase IV genes coupled with GyrA gene mutations alter DNA gyrase and lead to high-level fluoroquinolone resistance [19].
  • These A-ring-opened triterpenoids show in vitro cytotoxic activity against Hep-G2 and A-431 human cancer cell lines and are potent inhibitors of topoisomerase II [20].

Associations of gamma with chemical compounds


Analytical, diagnostic and therapeutic context of gamma

  • Sequence analysis of type II topoisomerase showed that most mutants had mutations in ParC at Ser79 or Asp83 and in GyrA at Ser81, while a few mutants had mutations in ParE or GyrB [23].
  • We have developed a PCR-oligonucleotide ligation assay to rapidly identify base substitutions in topoisomerase genes that are associated with quinolone resistance in clinical isolates of Streptococcus pneumoniae [24].
  • By immunoblotting using subunit-specific antisera, intracellular GyrA/GyrB levels were a modest threefold higher than those of ParC/ParE, most likely insufficient to allow selective drug action by counterbalancing the 20- to 40-fold preference for cleavable-complex formation through topoisomerase IV observed in vitro [25].
  • METHODS: All levofloxacin-resistant isolates were analysed by broth microdilution reference method for susceptibility to four fluoroquinolones, DNA sequencing of quinolone resistance determining region (QRDR) of topoisomerase IV and DNA gyrase genes, serotyping, and pulsed-field gel electrophoresis (PFGE) [26].


  1. Novel symmetric and asymmetric DNA scission determinants for Streptococcus pneumoniae topoisomerase IV and gyrase are clustered at the DNA breakage site. Leo, E., Gould, K.A., Pan, X.S., Capranico, G., Sanderson, M.R., Palumbo, M., Fisher, L.M. J. Biol. Chem. (2005) [Pubmed]
  2. Fluoroquinolone resistance in penicillin-resistant Streptococcus pneumoniae clones, Spain. de la Campa, A.G., Balsalobre, L., Ardanuy, C., Fenoll, A., Pérez-Trallero, E., Liñares, J. Emerging Infect. Dis. (2004) [Pubmed]
  3. In vitro antibacterial potency and spectrum of ABT-492, a new fluoroquinolone. Nilius, A.M., Shen, L.L., Hensey-Rudloff, D., Almer, L.S., Beyer, J.M., Balli, D.J., Cai, Y., Flamm, R.K. Antimicrob. Agents Chemother. (2003) [Pubmed]
  4. Gemifloxacin. Lowe, M.N., Lamb, H.M. Drugs (2000) [Pubmed]
  5. The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors. Li, Q., Mitscher, L.A., Shen, L.L. Medicinal research reviews. (2000) [Pubmed]
  6. In Vitro and In Vivo Activities of PD 0305970 and PD 0326448, New Bacterial Gyrase/Topoisomerase Inhibitors with Potent Antibacterial Activities versus Multidrug-Resistant Gram-Positive and Fastidious Organism Groups. Huband, M.D., Cohen, M.A., Zurack, M., Hanna, D.L., Skerlos, L.A., Sulavik, M.C., Gibson, G.W., Gage, J.W., Ellsworth, E., Stier, M.A., Gracheck, S.J. Antimicrob. Agents Chemother. (2007) [Pubmed]
  7. Dual Targeting of GyrB and ParE by a Novel Aminobenzimidazole Class of Antibacterial Compounds. 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. Antimicrob. Agents Chemother. (2007) [Pubmed]
  8. In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class. Mani, N., Gross, C.H., Parsons, J.D., Hanzelka, B., Müh, U., Mullin, S., Liao, Y., Grillot, A.L., Stamos, D., Charifson, P.S., Grossman, T.H. Antimicrob. Agents Chemother. (2006) [Pubmed]
  9. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Pan, X.S., Ambler, J., Mehtar, S., Fisher, L.M. Antimicrob. Agents Chemother. (1996) [Pubmed]
  10. Targeting of DNA gyrase in Streptococcus pneumoniae by sparfloxacin: selective targeting of gyrase or topoisomerase IV by quinolones. Pan, X.S., Fisher, L.M. Antimicrob. Agents Chemother. (1997) [Pubmed]
  11. Topoisomerase mutations associated with in vitro selection of resistance to moxifloxacin in Streptococcus pneumoniae. Houssaye, S., Gutmann, L., Varon, E. Antimicrob. Agents Chemother. (2002) [Pubmed]
  12. Contribution of the 8-methoxy group to the activity of gatifloxacin against type II topoisomerases of Streptococcus pneumoniae. Kishii, R., Takei, M., Fukuda, H., Hayashi, K., Hosaka, M. Antimicrob. Agents Chemother. (2003) [Pubmed]
  13. Cloning and nucleotide sequence of the DNA gyrase (gyrA) gene from Mycoplasma hominis and characterization of quinolone-resistant mutants selected in vitro with trovafloxacin. Bébéar, C.M., Grau, O., Charron, A., Renaudin, H., Gruson, D., Bébéar, C. Antimicrob. Agents Chemother. (2000) [Pubmed]
  14. Fluoroquinolone resistance associated with target mutations and active efflux in oropharyngeal colonizing isolates of viridans group streptococci. Guerin, F., Varon, E., Hoï, A.B., Gutmann, L., Podglajen, I. Antimicrob. Agents Chemother. (2000) [Pubmed]
  15. Ciprofloxacin dimers target gyrase in Streptococcus pneumoniae. Gould, K.A., Pan, X.S., Kerns, R.J., Fisher, L.M. Antimicrob. Agents Chemother. (2004) [Pubmed]
  16. Interspecies recombination contributes minimally to fluoroquinolone resistance in Streptococcus pneumoniae. Bast, D.J., de Azavedo, J.C., Tam, T.Y., Kilburn, L., Duncan, C., Mandell, L.A., Davidson, R.J., Low, D.E. Antimicrob. Agents Chemother. (2001) [Pubmed]
  17. Contribution of topoisomerase IV and DNA gyrase mutations in Streptococcus pneumoniae to resistance to novel fluoroquinolones. Pestova, E., Beyer, R., Cianciotto, N.P., Noskin, G.A., Peterson, L.R. Antimicrob. Agents Chemother. (1999) [Pubmed]
  18. Activities of fluoroquinolones against Streptococcus pneumoniae type II topoisomerases purified as recombinant proteins. Morrissey, I., George, J. Antimicrob. Agents Chemother. (1999) [Pubmed]
  19. Drug treatment of pneumococcal pneumonia in the elderly. Neralla, S., Meyer, K.C. Drugs & aging. (2004) [Pubmed]
  20. A phytochemical investigation of Alchornea latifolia. Setzer, W.N., Shen, X., Bates, R.B., Burns, J.R., McClure, K.J., Zhang, P., Moriarity, D.M., Lawton, R.O. Fitoterapia (2000) [Pubmed]
  21. Potent antipneumococcal activity of gemifloxacin is associated with dual targeting of gyrase and topoisomerase IV, an in vivo target preference for gyrase, and enhanced stabilization of cleavable complexes in vitro. Heaton, V.J., Ambler, J.E., Fisher, L.M. Antimicrob. Agents Chemother. (2000) [Pubmed]
  22. Selection of Streptococcus pneumoniae mutants having reduced susceptibility to moxifloxacin and levofloxacin. Li, X., Zhao, X., Drlica, K. Antimicrob. Agents Chemother. (2002) [Pubmed]
  23. In vitro selection of resistance to clinafloxacin, ciprofloxacin, and trovafloxacin in Streptococcus pneumoniae. Nagai, K., Davies, T.A., Pankuch, G.A., Dewasse, B.E., Jacobs, M.R., Appelbaum, P.C. Antimicrob. Agents Chemother. (2000) [Pubmed]
  24. PCR-oligonucleotide ligation assay for detection of point mutations associated with quinolone resistance in Streptococcus pneumoniae. Bui, M.H., Stone, G.G., Nilius, A.M., Almer, L., Flamm, R.K. Antimicrob. Agents Chemother. (2003) [Pubmed]
  25. 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. Pan, X.S., Yague, G., Fisher, L.M. Antimicrob. Agents Chemother. (2001) [Pubmed]
  26. Cross-resistance, relatedness and allele analysis of fluoroquinolone-resistant US clinical isolates of Streptococcus pneumoniae (1998-2000). Davies, T.A., Goldschmidt, R., Pfleger, S., Loeloff, M., Bush, K., Sahm, D.F., Evangelista, A. J. Antimicrob. Chemother. (2003) [Pubmed]
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