title: The Cfr rRNA methyltransferase confers resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics.
abstract: A novel multidrug resistance phenotype mediated by the Cfr rRNA methyltransferase is observed in Staphylococcus aureus and Escherichia coli. The cfr gene has previously been identified as a phenicol and lincosamide resistance gene on plasmids isolated from Staphylococcus spp. of animal origin and recently shown to encode a methyltransferase that modifies 23S rRNA at A2503. Antimicrobial susceptibility testing shows that S. aureus and E. coli strains expressing the cfr gene exhibit elevated MICs to a number of chemically unrelated drugs. The phenotype is named PhLOPSA for resistance to the following drug classes: Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics. Each of these five drug classes contains important antimicrobial agents that are currently used in human and/or veterinary medicine. We find that binding of the PhLOPSA drugs, which bind to overlapping sites at the peptidyl transferase center that abut nucleotide A2503, is perturbed upon Cfr-mediated methylation. Decreased drug binding to Cfr-methylated ribosomes has been confirmed by footprinting analysis. No other rRNA methyltransferase is known to confer resistance to five chemically distinct classes of antimicrobials. In addition, the findings described in this study represent the first report of a gene conferring transferable resistance to pleuromutilins and oxazolidinones.
authors.affiliation: Institute of Molecular Biology and Physiology, University of Copenhagen, Sølvgade 83 H, DK-1307 Copenhagen K, Denmark.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Long
authors.forename: Jacob
authors.initials: J
authors.lastname: Poehlsgaard
authors.forename: Corinna
authors.initials: C
authors.lastname: Kehrenberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwarz
authors.forename: Birte
authors.initials: B
authors.lastname: Vester
mesh_terms: D000900:Anti-Bacterial Agents / Q000145:classification / Q000494:pharmacology*; D002701:Chloramphenicol / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics*; D006801:Humans; D055231:Lincosamides; D018942:Macrolides / Q000494:pharmacology; D008780:Methyltransferases / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000494:pharmacology; D010458:Peptidyl Transferases / Q000378:metabolism; D011083:Polycyclic Compounds; D012270:Ribosomes / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D025364:Streptogramin A / Q000494:pharmacology; D013839:Thiamphenicol / Q000031:analogs & derivatives / Q000494:pharmacology; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D002701:Chloramphenicol; D004224:Diterpenes; D029968:Escherichia coli Proteins; D055231:Lincosamides; D018942:Macrolides; D008780:Methyltransferases; D023303:Oxazolidinones; D010458:Peptidyl Transferases; D011083:Polycyclic Compounds; D025364:Streptogramin A; D013839:Thiamphenicol; D000097567:Pleuromutilins; C035534:florfenicol; C534716:Cfr protein, E coli; C035181:rRNA (adenosine-O-2'-)methyltransferase