| Popis: |
This chapter concentrates on resistance to a subset of antibiotics, the 14-membered ring macrolides, and considers their fate as effective antibacterial agents now that resistance is widespread among bacterial pathogens. The ribosome target site for macrolides lies within the 23S rRNA at the peptidyltransferase center of the 50S subunit. Shortly after the introduction of erythromycin in therapy in the 1950s, resistance to the drug became widespread in numerous pathogens. The degree of resistance that is conferred seems to depend on the proportion of ribosomes that contain a modification (or mutation) at position 2058. Recent technical advances (not the least being reverse transcription-PCR methods) have made it possible to identify rRNA mutations that arise in pathogens during macrolide therapy. Pathogens that attain macrolide resistance by spontaneous rRNA mutations generally contain only one or two rrn operons. The occurrence of MLS resistance mutations is not limited to erythromycin derivatives nor to human pathogens but can occur in any species with a low rrn copy number that is exposed to macrolides. The details of the molecular contacts made between the Erm methyltransferases and the conserved rRNA motif await resolution by X-ray diffraction or NMR techniques. It can be hoped that determination of the three-dimensional structure of this motif will facilitate the design of compounds that will act as specific and effective competitive inhibitors of Erm methyltransferases. |
