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Gene Review

grlA  -  DNA topoisomerase IV subunit A

Staphylococcus aureus RF122

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Disease relevance of grlA


High impact information on grlA

  • There was no relationship between the time concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of mutations that appeared in grlA/B or gyrA [2].
  • The enrichment of subpopulations with mutations in grlA and low-level ciprofloxacin resistance also varied depending on the pharmacokinetic environment [3].
  • 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 [4].
  • Both the wild-type strain MT5 and grlA mutant MT5224c4 should be considered susceptible to both BMS-284756 and levofloxacin, and both quinolones are predicted to have clinical efficacy [5].
  • Exposure of this mutant to norfloxacin produced SA K1748, a derivative with raised fluoroquinolone MICs, found to be the result of a grlA mutation, and raised organic cation MICs [6].

Chemical compound and disease context of grlA


Biological context of grlA

  • The presence of wild-type grlB-grlA gene sequences in second-step mutants excluded involvement of topoisomerase IV in the small-colony phenotype [11].
  • The grlA point mutations of CAT-->CAC (His-77 [silent]), TCA-->CCA (Ser-81-->Pro), and ATA-->ATT (Ile-100 [silent]) were novel, as was the GAC-->GGC (Asp-73-->Gly) change in gyrA [12].
  • However, dominance by mutated grlA genes depended on gene dosage when bacteria were transformed with the grlA and grlB genes in combination [13].
  • Increased bacterial adhesion of the highly quinolone-resistant mutants, which contained combined mutations in grlA and gyrA, was associated with and explained by the overexpression of their fibronectin-binding proteins as assessed by Western ligand affinity blotting [14].
  • Quinolone-resistant gyrA mutants were easily isolated from a strain, S. aureus RN4220, carrying a plasmid with the mutated grlA gene, though this was not the case for other S. aureus strains lacking the plasmid [13].

Associations of grlA with chemical compounds

  • For fluoroquinolone-resistant but methicillin-susceptible strains, mutations in grlA alone are more common [15].
  • Those properties of gatifloxacin likely explain its good activity against quinolone-resistant clinical isolates of S. aureus harboring the grlA, gyrA, and/or norA mutations [16].
  • Second-step mutants were found to have, in addition to a mutation in grlA, reduced accumulation of norfloxacin or an alteration in GyrA at Ser-84 to Leu or Glu-88 to Lys [7].
  • For mutants with changes in both grlA and gyrA MICs were higher and were generally above the susceptibility breakpoint for ciprofloxacin, sparfloxacin, levofloxacin, and pefloxacin [9].
  • Ofloxacin and trovafloxacin selected most commonly for mutations in grlA, conferring substitutions for Ser-80 [17].

Regulatory relationships of grlA

  • The silent mutant allele of gyrA was present in a flqA background and expressed resistance only upon introduction of a grlA mutation [18].

Analytical, diagnostic and therapeutic context of grlA


  1. Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Ferrero, L., Cameron, B., Manse, B., Lagneaux, D., Crouzet, J., Famechon, A., Blanche, F. Mol. Microbiol. (1994) [Pubmed]
  2. Pharmacodynamic modeling of the evolution of levofloxacin resistance in Staphylococcus aureus. Campion, J.J., Chung, P., McNamara, P.J., Titlow, W.B., Evans, M.E. Antimicrob. Agents Chemother. (2005) [Pubmed]
  3. Evolution of ciprofloxacin-resistant Staphylococcus aureus in in vitro pharmacokinetic environments. Campion, J.J., McNamara, P.J., Evans, M.E. Antimicrob. Agents Chemother. (2004) [Pubmed]
  4. Topoisomerase targeting with and resistance to gemifloxacin in Staphylococcus aureus. Ince, D., Zhang, X., Silver, L.C., Hooper, D.C. Antimicrob. Agents Chemother. (2003) [Pubmed]
  5. Bactericidal activities of BMS-284756, a novel Des-F(6)-quinolone, against Staphylococcus aureus strains with topoisomerase mutations. Lawrence, L.E., Frosco, M., Ryan, B., Chaniewski, S., Yang, H., Hooper, D.C., Barrett, J.F. Antimicrob. Agents Chemother. (2002) [Pubmed]
  6. Evidence for the existence of a multidrug efflux transporter distinct from NorA in Staphylococcus aureus. Kaatz, G.W., Seo, S.M., O'Brien, L., Wahiduzzaman, M., Foster, T.J. Antimicrob. Agents Chemother. (2000) [Pubmed]
  7. Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus. Ferrero, L., Cameron, B., Crouzet, J. Antimicrob. Agents Chemother. (1995) [Pubmed]
  8. Association of mutations in grlA and gyrA topoisomerase genes with resistance to ciprofloxacin in epidemic and sporadic isolates of methicillin-resistant Staphylococcus aureus. Deplano, A., Zekhnini, A., Allali, N., Couturier, M., Struelens, M.J. Antimicrob. Agents Chemother. (1997) [Pubmed]
  9. Activities of trovafloxacin compared with those of other fluoroquinolones against purified topoisomerases and gyrA and grlA mutants of Staphylococcus aureus. Gootz, T.D., Zaniewski, R.P., Haskell, S.L., Kaczmarek, F.S., Maurice, A.E. Antimicrob. Agents Chemother. (1999) [Pubmed]
  10. Quinolone resistance in Staphylococci: activities of new nonfluorinated quinolones against molecular targets in whole cells and clinical isolates. Roychoudhury, S., Catrenich, C.E., McIntosh, E.J., McKeever, H.D., Makin, K.M., Koenigs, P.M., Ledoussal, B. Antimicrob. Agents Chemother. (2001) [Pubmed]
  11. Small-colony mutants of Staphylococcus aureus allow selection of gyrase-mediated resistance to dual-target fluoroquinolones. Pan, X.S., Hamlyn, P.J., Talens-Visconti, R., Alovero, F.L., Manzo, R.H., Fisher, L.M. Antimicrob. Agents Chemother. (2002) [Pubmed]
  12. Detection of grlA and gyrA mutations in 344 Staphylococcus aureus strains. Wang, T., Tanaka, M., Sato, K. Antimicrob. Agents Chemother. (1998) [Pubmed]
  13. Alterations in the DNA topoisomerase IV grlA gene responsible for quinolone resistance in Staphylococcus aureus. Yamagishi, J., Kojima, T., Oyamada, Y., Fujimoto, K., Hattori, H., Nakamura, S., Inoue, M. Antimicrob. Agents Chemother. (1996) [Pubmed]
  14. Increased expression of fibronectin-binding proteins by fluoroquinolone-resistant Staphylococcus aureus exposed to subinhibitory levels of ciprofloxacin. Bisognano, C., Vaudaux, P.E., Lew, D.P., Ng, E.Y., Hooper, D.C. Antimicrob. Agents Chemother. (1997) [Pubmed]
  15. Topoisomerase mutations in fluoroquinolone-resistant and methicillin-susceptible and -resistant clinical isolates of Staphylococcus aureus. Kaatz, G.W., Seo, S.M. Antimicrob. Agents Chemother. (1998) [Pubmed]
  16. Antibacterial activity of gatifloxacin (AM-1155, CG5501, BMS-206584), a newly developed fluoroquinolone, against sequentially acquired quinolone-resistant mutants and the norA transformant of Staphylococcus aureus. Fukuda, H., Hori, S., Hiramatsu, K. Antimicrob. Agents Chemother. (1998) [Pubmed]
  17. Selection of moxifloxacin-resistant Staphylococcus aureus compared with five other fluoroquinolones. Griggs, D.J., Marona, H., Piddock, L.J. J. Antimicrob. Chemother. (2003) [Pubmed]
  18. Quinolone resistance mutations in topoisomerase IV: relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus. Ng, E.Y., Trucksis, M., Hooper, D.C. Antimicrob. Agents Chemother. (1996) [Pubmed]
  19. Real-time PCR assay for detection of fluoroquinolone resistance associated with grlA mutations in Staphylococcus aureus. Lapierre, P., Huletsky, A., Fortin, V., Picard, F.J., Roy, P.H., Ouellette, M., Bergeron, M.G. J. Clin. Microbiol. (2003) [Pubmed]
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