INDUCIBLE NORA-MEDIATED MULTIDRUG-RESISTANCE IN STAPHYLOCOCCUS-AUREUS

The NorA protein of Staphylococcus aureus mediates the active efflux o f hydrophilic fluoroquinolones from the cell, conferring low-level res istance upon the organism, This protein also is capable of transportin g 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 cytoplas mic membrane, is felt to be the mechanism by which strains possessing such changes resist fluoroquinolones. S. aureus SA-1199 and its in viv o-selected derivative SA-1199B are fluoroquinolone-susceptible and -re sistant isolates, respectively; SA-1199B resists hydrophilic fluoroqui nolones via a NorA-mediated mechanism in a constitutive manner, SA-119 9-3 is an in vitro-produced derivative of SA-1199 in which NorA-mediat ed multidrug resistance is expressed inducibly. Compared with organism s exposed to subinhibitory concentrations of a NorA substrate for the first time, preexposure of SA-1199-3 to such a compound followed by gr owth 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 o f logarithmic growth, The uptake of radiolabeled fluoroquinolone is ma rkedly reduced by preexposure of SA-1199-3 to NorA substrates; such pr ior exposure also results in a dramatic increase in RNA transcripts th at hybridize with a norA probe, Preexposure of SA-1199 and SA-1199B to such substrates results in small increases or no increases in these t ranscripts, No sequence differences between SA-1199 and SA-1199-3 with in the norA gene or flanking DNA were found, It appears likely that th e regulation of nor A in SA-1199-3, which mag be effected by one or mo re genetic loci outside the norA region of the chromosome, differs fro m that of SA-1199 and SA-1199B.