LINEZOLID RESISTANCE MUTATIONS IN GRAM-POSITIVE BACTERIA

摘要

Linezolid is a member of a novel class of antibiotics, with resistance already being reported. We used wholegenome sequencing on three independent Streptococcus pneumoniae strains made resistant to linezolid in vitro in a step-by-step fashion. Analysis of the genome assemblies revealed mutations in the 23S rRNA gene in all mutants including, notably, G2576T, a previously recognized resistance mutation. Mutations in an additional 31 genes were also found in at least one of the three sequenced genomes. We concentrated our efforts on three new mutations that were found in at least two independent mutants. All three mutations were experimentally confirmed to be involved in antibiotic resistance. Mutations upstream of the ABC transporter genes SP_1114 and SP_2075 were correlated with increased expression of these genes and neighboring genes of the same operon. The hypothetical protein SP_0373 contains an RNA methyltransferase domain, and mutations within that domain were found in all S. pneumoniae linezolid-resistant strains. Interestingly, the SP_0373 ortholog was also mutated in a linezolid-resistant clinical Staphylococcus aureus isolate.