Inducible NorA-mediated multidrug resistance in Staphylococcus aureus

Antimicrob Agents Chemother. 1995 Dec;39(12):2650-5. doi: 10.1128/AAC.39.12.2650.

Abstract

The NorA protein of Staphylococcus aureus mediates the active efflux of hydrophilic fluoroquinolones from the cell, conferring low-level resistance upon the organism. The protein also is capable of transporting additional structurally diverse compounds, indicating that it has a broad substrate specificity. 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. S. aureus SA-1199 and its in vivo-selected derivative SA-1199B are fluoroquinolone-susceptible and -resistant isolates, respectively; SA-1199B resists hydrophilic fluoroquinolones via a NorA-mediated mediated mechanism in a constitutive manner. SA-1199-3 is an in vitro-produced derivative of SA-1199 in which NorA-mediated multidrug resistance is expressed inducibly. Compared with organisms exposed to subinhibitory concentrations of a NorA substrate for the first time, preexposure of SA-1199-3 to such a compound followed by growth in the presence of that substrate results in the elimination of a 2- to 6-h period of organism killing that occurs prior to the onset of logarithmic growth. The uptake of radiolabeled fluoroquinolone is markedly reduced by preexposure of SA-1199-3 to NorA substrates: such prior exposure also results in a dramatic increase in RNa transcripts that hybridize with a norA probe. Preexposure of SA-1199 and SA-1199B to such substrates results in small increases or no increases in these transcripts. No sequence differences between SA-1199 and SA-1199-3 within the norA gene or flanking DNA were found. It appears likely that the regulation of norA in SA-1193, which may be effected by one or more genetic loci outside the norA region of the chromosome, differs from that of SA-1199 and SA-1199B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Infective Agents / metabolism
  • Anti-Infective Agents / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Base Sequence
  • Blotting, Northern
  • DNA, Bacterial / biosynthesis
  • Drug Resistance, Microbial / genetics
  • Drug Resistance, Multiple / genetics*
  • Enoxacin / metabolism
  • Enoxacin / pharmacology
  • Microbial Sensitivity Tests
  • Molecular Sequence Data
  • Multidrug Resistance-Associated Proteins
  • Mutation
  • Norfloxacin / metabolism
  • Norfloxacin / pharmacology
  • Plasmids
  • Polymerase Chain Reaction
  • RNA, Bacterial / biosynthesis
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / genetics
  • Staphylococcus aureus / metabolism*

Substances

  • Anti-Infective Agents
  • Bacterial Proteins
  • DNA, Bacterial
  • Multidrug Resistance-Associated Proteins
  • RNA, Bacterial
  • NorA protein, Staphylococcus
  • Enoxacin
  • Norfloxacin