Macrolide resistance based on the Erm-mediated rRNA methylation.
Macrolide, lincosamide and streptogramin B (MLSB) antibiotics are extensively used for the treatment of wide variety of clinically important Gram-positive bacteria. MLSB antibiotics inhibit protein biosynthesis by targeting the peptidyl transferase centre within the 50S ribosomal subunit. The most widespread mechanism of bacterial resistance to MLSB antibiotics, reported early after their introduction into clinical practice is the modification of the target site exhibited by a family of rRNA methyltransferases designated Erm. Using S-adenosyl-L-methionine, Erm enzymes catalyze mono- or dimethylation of a specific adenine residue in the 23S rRNA. The methyl group sterically hinders the MLSB binding site and disrupts the hydrogen bonding between the macrolides and the rRNA, thus rendering bacteria resistant. This review summarizes the current understanding of Erm-mediated resistance, in light of high-resolution structural data of bacterial ribosome and with specific focus on the results of recent genetic, biochemical and structural studies of Erm methyltransferases and their cognate rRNA substrate. Although many features of MLSB resistance remain indistinct, the present knowledge can now serve as the guidance for development of both new antimicrobial drugs and potential inhibitors of Erm enzymes, hence providing a new lead to solve the urgent problem of the macrolide resistance based on the ribosome methylation.
Maravić
G
G
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovacicća 1, 10000 Zagreb, Croatia. gordana@pharma.hr
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008745:Methylation; D012335:RNA, Ribosomal / Q000235:genetics*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000235:genetics*
D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D018942:Macrolides; D012335:RNA, Ribosomal; D014157:Transcription Factors