Novel Ribosomal Mutations in Staphylococcus aureus Strains Identified through Selection with the Oxazolidinones Linezolid and Torezolid (TR-700)

作者：Jeffrey B. Locke, M.T. Hilgers, Karen Joy Shaw · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2009 · DOI：10.1128/aac.00871-09 · 被引用次数：209 · 研究领域：Antimicrobial Resistance in Staphylococcus、RNA and protein synthesis mechanisms、Bacterial Genetics and Biotechnology

TR-700 (torezolid), the active moiety of the novel oxazolidinone phosphate prodrug TR-701, is highly potent against gram-positive pathogens, including strains resistant to linezolid (LZD). Here we investigated the potential of Staphylococcus aureus strains ATCC 29213 (methicillin-susceptible S. aureus [MSSA]) and ATCC 33591 (methicillin-resistant S. aureus [MRSA]) to develop resistance to TR-700. The spontaneous frequencies of mutation of MSSA 29213 and MRSA 33591 resulting in reduced susceptibility to TR-700 at 2 x the MIC were 1.1 x 10(-10) and 1.9 x 10(-10), respectively. These values are approximately 16-fold lower than the corresponding LZD spontaneous mutation frequencies of both strains. Following 30 serial passages in the presence of TR-700, the MIC for MSSA 29213 remained constant (0.5 microg/ml) while increasing eightfold (0.25 to 2.0 microg/ml) for MRSA 33591. Serial passage of MSSA 29213 and MRSA 33591 in LZD resulted in 64- and 32-fold increases in LZD resistance (2 to 128 microg/ml and 1 to 32 microg/ml, respectively). Domain V 23S rRNA gene mutations (Escherichia coli numbering) found in TR-700-selected mutants included T2500A and a novel coupled T2571C/G2576T mutation, while LZD-selected mutants included G2447T, T2500A, and G2576T. We also identified mutations correlating with decreased susceptibility to TR-700 and LZD in the rplC and rplD genes, encoding the 50S ribosomal proteins L3 and L4, respectively. L3 mutations included Gly152Asp, Gly155Arg, Gly155Arg/...