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Gene Review

norA  -  quinolone resistance protein

Staphylococcus aureus RF122

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Disease relevance of norA


High impact information on norA

  • NorC, a new efflux pump, like NorB, contributes to quinolone resistance that includes resistance to moxifloxacin and sparfloxacin in Staphylococcus aureus. norC expression, like that of norB and tet38, is negatively regulated by MgrA, and overexpression of both norC and norB contributes to the quinolone resistance phenotype of an mgrA mutant [6].
  • A chromosomal norA::lacZ transcriptional fusion was constructed in different S. aureus strains, and allele replacement was used to define the relevance of promoter region sequences to norA expression [7].
  • The flqB position of norA mRNA is part of a conserved imperfect inverted repeat; it is feasible that this motif could be a binding site for a norA regulatory protein [7].
  • Disruption of a near-perfect inverted repeat or other putative regulatory protein binding sites did not affect norA transcription, but the repressive effect of mgrA overexpression was blunted in these mutants [7].
  • We further characterized resistant strains selected with the combination of ciprofloxacin and WCK-1734 and found evidence to suggest the existence of novel mutational mechanisms for low-level quinolone resistance [8].

Chemical compound and disease context of norA


Biological context of norA

  • The norA gene of one transformant carried a single base deletion (ATACAAT to AACAAT; the deleted base is underlined) in the putative--10 Pribnow box resulting in a promoter down-regulatory mutation; a second plasmid had acquired a frameshift producing a null mutation at codon 112 [2].
  • Determination of the nucleotide sequence of norA1199 revealed an encoded 388-amino-acid hydrophobic polypeptide 95% homologous with the norA-encoded protein [13].
  • However, increased expression of norA can occur independently of this mutation, suggesting that a regulatory locus for this gene exists elsewhere on the chromosome [14].
  • These mutations override the dual resistance-growth-inhibitory phenotype of high-copy-number norA plasmids [2].
  • The results have implications for using the standard E. coli HB101 system to assess NorA function and potentially for plasmid-borne transmission of norA-mediated drug resistance [2].

Anatomical context of norA

  • Increased transcription of the norA gene, leading to a greater quantity of the NorA protein within the cytoplasmic membrane, is felt to be the mechanism by which strains possessing such changes resist fluoroquinolones [15].

Associations of norA with chemical compounds

  • Increased ciprofloxacin resistance correlated with norA transcript levels seen by Northern (RNA) analysis [2].
  • Gatifloxacin possessed potent activity (MIC, 0.39 microg/ml) against the NorA-overproducing strain S. aureus NY12, the norA transformant, which was slightly lower than that against the parent strain SA113 [9].
  • Increased expression of norA in S. aureus had no effect on the accumulation of moxifloxacin [16].
  • RESULTS AND CONCLUSIONS: Exposure to several substrates significantly increased norA expression whereas salicylate and osmotic stress had no effect and no stable soluble factor affecting norA expression was detectable [17].
  • The uptake of a hydrophilic quinolone, enoxacin, by S. aureus harboring a plasmid carrying the norA gene was about 50% that by the parent strain lacking the plasmid, but it increased to almost the same level as that by the latter strain with carbonyl cyanide m-chlorophenyl hydrazone [18].

Other interactions of norA

  • 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 [9].
  • Two genes previously associated with fluoroquinolone resistance, the gyrA gene of DNA gyrase and the norA gene (associated with decreased drug accumulation), were localized to the G and D fragments, respectively [19].
  • Expression studies with an arlS mutant revealed that the norA promoter is ArlS dependent [20].
  • No mutations were observed in either the gyrB or norA genes [21].
  • Overexpression of norR in sarA and agr mutants did not alter quinolone sensitivity or levels of norA transcription, indicating that the presence of these two global regulatory systems is necessary for NorR to affect the expression of norA [22].

Analytical, diagnostic and therapeutic context of norA


  1. Quinolone susceptibility of norA-disrupted Staphylococcus aureus. Yamada, H., Kurose-Hamada, S., Fukuda, Y., Mitsuyama, J., Takahata, M., Minami, S., Watanabe, Y., Narita, H. Antimicrob. Agents Chemother. (1997) [Pubmed]
  2. NorA plasmid resistance to fluoroquinolones: role of copy number and norA frameshift mutations. Sun, L., Sreedharan, S., Plummer, K., Fisher, L.M. Antimicrob. Agents Chemother. (1996) [Pubmed]
  3. The multidrug efflux transporter of Bacillus subtilis is a structural and functional homolog of the Staphylococcus NorA protein. Neyfakh, A.A. Antimicrob. Agents Chemother. (1992) [Pubmed]
  4. Rapid emergence of quinolone resistance in cirrhotic patients treated with norfloxacin to prevent spontaneous bacterial peritonitis. Dupeyron, C., Mangeney, N., Sedrati, L., Campillo, B., Fouet, P., Leluan, G. Antimicrob. Agents Chemother. (1994) [Pubmed]
  5. Selection of a gyrA mutant of Mycobacterium tuberculosis resistant to fluoroquinolones during treatment with ofloxacin. Cambau, E., Sougakoff, W., Besson, M., Truffot-Pernot, C., Grosset, J., Jarlier, V. J. Infect. Dis. (1994) [Pubmed]
  6. NorC, a new efflux pump regulated by MgrA of Staphylococcus aureus. Truong-Bolduc, Q.C., Strahilevitz, J., Hooper, D.C. Antimicrob. Agents Chemother. (2006) [Pubmed]
  7. Effect of promoter region mutations and mgrA overexpression on transcription of norA, which encodes a Staphylococcus aureus multidrug efflux transporter. Kaatz, G.W., Thyagarajan, R.V., Seo, S.M. Antimicrob. Agents Chemother. (2005) [Pubmed]
  8. 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. Strahilevitz, J., Hooper, D.C. Antimicrob. Agents Chemother. (2005) [Pubmed]
  9. 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]
  10. Genetic evidence for a role of parC mutations in development of high-level fluoroquinolone resistance in Escherichia coli. Heisig, P. Antimicrob. Agents Chemother. (1996) [Pubmed]
  11. Emergence of quinolone resistance among clinical isolates of methicillin-resistant Staphylococcus aureus in Ontario, Canada. Harnett, N., Brown, S., Krishnan, C. Antimicrob. Agents Chemother. (1991) [Pubmed]
  12. 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. Strahilevitz, J., Truong-Bolduc, Q.C., Hooper, D.C. Antimicrob. Agents Chemother. (2005) [Pubmed]
  13. Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus. Kaatz, G.W., Seo, S.M., Ruble, C.A. Antimicrob. Agents Chemother. (1993) [Pubmed]
  14. Mechanisms of fluoroquinolone resistance in genetically related strains of Staphylococcus aureus. Kaatz, G.W., Seo, S.M. Antimicrob. Agents Chemother. (1997) [Pubmed]
  15. Inducible NorA-mediated multidrug resistance in Staphylococcus aureus. Kaatz, G.W., Seo, S.M. Antimicrob. Agents Chemother. (1995) [Pubmed]
  16. Antimicrobial activity and accumulation of moxifloxacin in quinolone-susceptible bacteria. Piddock, L.J., Jin, Y.F. J. Antimicrob. Chemother. (1999) [Pubmed]
  17. Effect of substrate exposure and other growth condition manipulations on norA expression. Kaatz, G.W., Seo, S.M. J. Antimicrob. Chemother. (2004) [Pubmed]
  18. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. Yoshida, H., Bogaki, M., Nakamura, S., Ubukata, K., Konno, M. J. Bacteriol. (1990) [Pubmed]
  19. A novel locus conferring fluoroquinolone resistance in Staphylococcus aureus. Trucksis, M., Wolfson, J.S., Hooper, D.C. J. Bacteriol. (1991) [Pubmed]
  20. Expression of the multidrug resistance transporter NorA from Staphylococcus aureus is modified by a two-component regulatory system. Fournier, B., Aras, R., Hooper, D.C. J. Bacteriol. (2000) [Pubmed]
  21. Mutations in the gyrA and grlA genes of quinolone-resistant clinical isolates of methicillin-resistant Staphylococcus aureus. Takahata, M., Yonezawa, M., Kurose, S., Futakuchi, N., Matsubara, N., Watanabe, Y., Narita, H. J. Antimicrob. Chemother. (1996) [Pubmed]
  22. Characterization of NorR protein, a multifunctional regulator of norA expression in Staphylococcus aureus. Truong-Bolduc, Q.C., Zhang, X., Hooper, D.C. J. Bacteriol. (2003) [Pubmed]
  23. Introduction of a norA promoter region mutation into the chromosome of a fluoroquinolone-susceptible strain of Staphylococcus aureus using plasmid integration. Kaatz, G.W., Seo, S.M., Foster, T.J. Antimicrob. Agents Chemother. (1999) [Pubmed]
  24. NorA functions as a multidrug efflux protein in both cytoplasmic membrane vesicles and reconstituted proteoliposomes. Yu, J.L., Grinius, L., Hooper, D.C. J. Bacteriol. (2002) [Pubmed]
  25. 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]
  26. Molecular epidemiology of quinolone resistance and comparative in vitro activities of new quinolones against European Staphylococcus aureus isolates. Schmitz, F.J., Fluit, A.C., Brisse, S., Verhoef, J., Köhrer, K., Milatovic, D. FEMS Immunol. Med. Microbiol. (1999) [Pubmed]
  27. Widespread emergence of methicillin resistance in community-acquired Staphylococcus aureus infections in Denver. Clancy, M.J., Graepler, A., Breese, P.E., Price, C.S., Burman, W.J. South. Med. J. (2005) [Pubmed]
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