Analysis of the effects of inhibitors of homologous recombination in ribosomal mutations involved in resistance to linezolid in gram-positive cocci

Abstract

Linezolid, the first agent of the oxazolidinone class to be introduced clinically, is potentially active against important bacterial pathogens, including methicillin-resistant Staphylococcus spp. and vancomycin-resistant Enterococcus spp.. This new oxazolidinone inhibits protein biosynthesis by binding to the peptidyl transferase center (PTC) of the 50S subunit of the bacterial ribosome. Linezolid resistance can be mediated by the cfr-encoded product or by mutations in the ribosomal proteins L3, L4 and L22, however, the most common mechanism of resistance involves mutations in the central loop of domain V of the 23S rRNA gene, being G2576T reported more frequently in linezolid-resistant clinical isolates. A correlation between the increased number of mutated rRNA operons and high levels of minimum inhibitory concentrations (MIC) for linezolid has been found. RecA-mediated gene conversion was shown to be responsible for conversion of the wild-type allele into the mutant allele at a high frequency. In this work, we will evaluate different serum concentrations of linezolid in combination with inhibitors of homologous recombination in the occurrence of mutations in the V domain of multiple alleles of the 23S rRNA gene and in the ribosomal proteins close to the binding site of linezolid. It is intended to define any inhibitor of the process of homologous recombination that may reduce the emergence of linezolid resistance in Gram-positive cocci. (AU)