Mutations in ribosomal protein L3 are associated with oxazolidinone resistance in staphylococci of clinical origin

Abstract

Following recent reports of ribosomal protein L3 mutations in laboratory-derived linezolid-resistant (LZD(r)) Staphylococcus aureus, we investigated whether similar mutations were present in LZD(r) staphylococci of clinical origin. Sequence analysis of a variety of LZD(r) isolates revealed two L3 mutations, DeltaSer145 (S. aureus NRS127) and Ala157Arg (Staphylococcus epidermidis 1653059), both occurring proximal to the oxazolidinone binding site in the peptidyl transferase center. The oxazolidinone torezolid maintained a >or=8-fold potency advantage over linezolid for both strains.

FIG. 1.

Structural analysis of ribosomal mutations in clinical LZD^r strains. Mutations of ribosomal protein L3 (ΔSer145 and Ala157Arg) and 23S rRNA (G2447U) are shown in red. A PTC-bound LZD molecule is shown in salmon. 23S rRNA bases A2503 (site of methylation by Cfr), 2504 to 2506 (key residues lining the oxazolidinone binding site in the PTC), and ribosomal protein L4 are shown for reference. Images were generated with PyMOL (6), using the coordinates of the D. radiodurans LZD-bound 50S subunit (31). In the D. radiodurans L3 protein, residue 157 (staphylococcal numbering) is an arginine that interacts with the sugar-phosphate backbone between G2505 and U2506. Although the identity of this residue varies across species, it maintains a similar orientation with respect to G2505/U2506 in the disparate orthologs for which crystal structures exist (D. radiodurans, Haloarcula marismortui, and E. coli).