Inducible NorA-mediated multidrug resistance in Staphylococcus aureus.
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.
Kaatz
G W
GW
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. US001617@interramp.com
Seo
S M
SM
D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D015152:Blotting, Northern; D004269:DNA, Bacterial / Q000096:biosynthesis; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015365:Enoxacin / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009154:Mutation; D009643:Norfloxacin / Q000378:metabolism / Q000494:pharmacology; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012329:RNA, Bacterial / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D015365:Enoxacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009643:Norfloxacin; D012329:RNA, Bacterial; C075040:NorA protein, Staphylococcus