Molecular characterization of ketolide-resistant erm(A)-carrying Staphylococcus aureus isolates selected in vitro by telithromycin, ABT-773, quinupristin and clindamycin

The aim of this study was to investigate whether a Staphylococcus aureus strain that carried an inducibly expressed erm(A) gene might exhibit resistance to the non-inducers telithromycin, ABT-773, clindamycin, quinupristin, dalfopristin or the combination quinupristin-dalfopristin after incubation in the presence of inhibitory concentrations of any of these compounds. Whenever resistant mutants were obtained, these were investigated for the molecular basis of the altered resistance phenotype. Resistant mutants were not selected with dalfopristin or quinupristin-dalfopristin, but were obtained with the other four agents. Irrespective of which drug was used for selection, all mutants were cross-resistant to clindamycin, quinupristin, telithromycin and ABT-773, and exhibited structural alterations in the erm(A) translational attenuator. The structural alterations observed included deletions of 14, 83, 121, 131, 147 or 157 bp, three different tandem duplications of 23, 25 or 26 bp, two different types of point mutation, as well as the insertion of IS256. All these alterations either completely prevented the formation of mRNA secondary structures in the erm(A) regulatory region or favoured the formation of those mRNA secondary structures that allowed translation of the erm(A) transcripts. Deletions, which were observed in almost two-thirds of the mutants, might be explained by illegitimate recombination between different parts of the erm(A) regulatory region.