title: Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens.
abstract: A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.
authors.affiliation: Infectious Disease Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-3537, USA. zhenkun.ma@abbott.com
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.forename: R F
authors.initials: RF
authors.lastname: Clark
authors.forename: A
authors.initials: A
authors.lastname: Brazzale
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: M J
authors.initials: MJ
authors.lastname: Rupp
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Griesgraber
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Yong
authors.forename: L T
authors.initials: LT
authors.lastname: Phan
authors.forename: P A
authors.initials: PA
authors.lastname: Nemoto
authors.forename: D T
authors.initials: DT
authors.lastname: Chu
authors.forename: J J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: P
authors.initials: P
authors.lastname: Zhong
authors.forename: Z
authors.initials: Z
authors.lastname: Cao
authors.forename: A M
authors.initials: AM
authors.lastname: Nilius
authors.forename: V D
authors.initials: VD
authors.lastname: Shortridge
authors.forename: R
authors.initials: R
authors.lastname: Flamm
authors.forename: M
authors.initials: M
authors.lastname: Mitten
authors.forename: J
authors.initials: J
authors.lastname: Meulbroek
authors.forename: P
authors.initials: P
authors.lastname: Ewing
authors.forename: J
authors.initials: J
authors.lastname: Alder
authors.forename: Y S
authors.initials: YS
authors.lastname: Or
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002474:Cell-Free System; D018432:Drug Resistance, Multiple; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000187:drug effects; D048628:Ketolides; D008168:Lung / Q000382:microbiology; D051379:Mice; D008958:Models, Molecular; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D012270:Ribosomes / Q000187:drug effects / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000648:ultrastructure; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D002219:Carbamates; D048628:Ketolides; D011500:Protein Synthesis Inhibitors; D004917:Erythromycin; C405499:cethromycin