title: Induction of ribosome methylation in MLS-resistant Streptococcus pneumoniae by macrolides and ketolides.
abstract: One major mechanism for resistance to macrolide antibiotics in Streptococcus pneumoniae is MLS (macrolide, lincosamide, and streptogramin B) resistance, manifested when the 23S rRNA is methylated by the product of an erm gene. This modification results in the decreased binding of all known macrolide, lincosamide, and streptogramin B antibiotics to the ribosome. More than 30 ermAM-containing clinical isolates of S. pneumoniae were examined in our lab and showed high-level resistance (MIC > or =128 microg/ml) to erythromycin, azithromycin, tylosin, clindamycin, and ketolide (macrolides that lack the cladinose sugar) TE-802. We found that the new generation of ketolides A965 and A088 displayed variable activity against the same group of resistant S. pneumoniae strains. To understand the basis of variability of the minimal inhibitory concentration (MIC) values of A965 and A088, we examined the effects of a series of macrolides and ketolides on the level of 23S rRNA methylation in five ermAM-containing resistant S. pneumoniae isolates. We show here that the basal levels of ribosomal methylation vary from strain to strain. The level of rRNA methylation can be strongly induced by erythromycin, azithromycin, and TE-802, resulting in high-level of resistance to these compounds. Ketolide A965 and A088, however, are weak inducers at sub-MIC drug concentrations, therefore showing variable activities in strains with differential methylation levels.
authors.affiliation: AP52-1N, Antibacterial Department, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhong
authors.forename: Z
authors.initials: Z
authors.lastname: Cao
authors.forename: R
authors.initials: R
authors.lastname: Hammond
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Beyer
authors.forename: V D
authors.initials: VD
authors.lastname: Shortridge
authors.forename: L Y
authors.initials: LY
authors.lastname: Phan
authors.forename: S
authors.initials: S
authors.lastname: Pratt
authors.forename: J
authors.initials: J
authors.lastname: Capobianco
authors.forename: K A
authors.initials: KA
authors.lastname: Reich
authors.forename: R K
authors.initials: RK
authors.lastname: Flamm
authors.forename: Y S
authors.initials: YS
authors.lastname: Or
authors.forename: L
authors.initials: L
authors.lastname: Katz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D055231:Lincosamides; D018942:Macrolides; D008745:Methylation; D012336:RNA, Ribosomal, 16S / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics; D014769:Virginiamycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D055231:Lincosamides; D018942:Macrolides; D012336:RNA, Ribosomal, 16S; D014769:Virginiamycin