title: In vitro antibacterial activity of α-methoxyimino acylide derivatives against macrolide-resistant pathogens and mutation analysis in 23S rRNA.
abstract: We characterized in vitro activities of α-methoxyimino acylides against macrolide-resistant clinical isolates of Streptococcus pneumoniae, Streptococcus pyogenes and Mycoplasma pneumoniae with ribosome modification or substitution and selected acylide-resistant mutants to clarify the binding point of the acylides. The acylides had low MICs against erm(B) gene-containing S. pneumoniae and S. pyogenes (MIC90s, 1-4 μg ml-1). For M. pneumoniae, although they had poor potencies against macrolide-resistant strains with the A2058G (Escherichia coli numbering) mutation in 23S rRNA (MICs, >32 μg ml-1), one of them showed in vitro activities against macrolide-resistant strains with the A2058U or A2059G mutations (MICs, 0.5-1 μg ml-1). These A2058U and A2059G mutant strains were used for the selection of acylide-resistant mutants. A genetic analysis showed that new point mutations in acylide-resistant mutants were found at G2576 in domain V of 23S rRNA and at Lys90 in L22 ribosomal protein. Furthermore, a molecular modeling study revealed that G2505/C2610, which enables stacking with G2576, might interact with a pyridyl moiety or an α-methoxyimino group at the 3-position of acylides. The α-methoxyimino acylides were shown to possess a tertiary binding point at G2505/C2610 in 23S rRNA. Our results suggest that α-methoxyimino acylides represent significant progress in macrolide antimicrobials.
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.|Department of Infection Control Science, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugiyama
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Yoshida
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ueki
authors.affiliation: Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Manaka
authors.affiliation: Department of Infection Control Science, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hiramatsu
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics*; D018942:Macrolides / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009154:Mutation; D009177:Mycoplasma pneumoniae / Q000187:drug effects / Q000235:genetics; D012338:RNA, Ribosomal, 23S / Q000235:genetics*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000235:genetics; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D012338:RNA, Ribosomal, 23S