title: Resistance to Macrolide Antibiotics in Public Health Pathogens.
abstract: Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome's interaction with the antibiotic. Alternatively, mono- or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) + msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 2'-hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquired genes are regulated by either translation or transcription attenuation, largely because cells are less fit when these genes, especially the rRNA methyltransferases, are highly induced or constitutively expressed. The induction of gene expression is cleverly tied to the mechanism of action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequences of nascent polypeptides to promote transcription or translation of downstream sequences.
authors.affiliation: Tetraphase Pharmaceuticals, Watertown, Massachusetts 02472.
authors.forename: Corey
authors.initials: C
authors.lastname: Fyfe
authors.affiliation: Tetraphase Pharmaceuticals, Watertown, Massachusetts 02472.
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.affiliation: Tetraphase Pharmaceuticals, Watertown, Massachusetts 02472.
authors.forename: Kathy
authors.initials: K
authors.lastname: Kerstein
authors.affiliation: Tetraphase Pharmaceuticals, Watertown, Massachusetts 02472.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sutcliffe
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D018942:Macrolides / Q000494:pharmacology*; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics; D008826:Microbial Sensitivity Tests; D012329:RNA, Bacterial / Q000235:genetics; D012338:RNA, Ribosomal, 23S / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D012329:RNA, Bacterial; D012338:RNA, Ribosomal, 23S; D012269:Ribosomal Proteins; D008780:Methyltransferases; C035181:rRNA (adenosine-O-2'-)methyltransferase