title: Novel semisynthetic derivative of antibiotic Eremomycin active against drug-resistant gram-positive pathogens including Bacillus anthracis.
abstract: Five adamantyl-containing carboxamides of eremomycin or vancomycin were synthesized and their antibacterial activities against some Gram-positive clinical isolates were investigated in vitro and in vivo. The adamantyl-2 amide of glycopeptide antibiotic eremomycin (1a in Chart 1, AN0900) was the most active compound and showed high activity against several Gram-positive pathogens: vancomycin-susceptible staphylococci and enterococci, glycopeptide-intermediate-resistant Staphylococcus aureus, and glycopeptide-resistant enterococci. Compound 1a was equally active in vitro against both Ciprofloxacin-susceptible and -resistant Bacillus anthracis strains (MICs 0.25-0.5 microg/mL). It was distinguished by having a 2.8 h half-life (t1/2) in mice and a volume of distribution of 2.18 L/kg. Compound 1a was active against Staphylococcus aureus in mice (iv) and provided complete protection against a lethal intravenous challenge with vegetative B. anthracis bacilli and also in a murine pulmonary anthrax model in which mice were challenged with Bacillus anthracis spores.
authors.affiliation: Anacor Pharmaceuticals, Inc., 1060 East Meadow Circle, Palo Alto, California 94303, USA.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Maples
authors.forename: Conrad
authors.initials: C
authors.lastname: Wheeler
authors.forename: Emily
authors.initials: E
authors.lastname: Ip
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: Daniel
authors.initials: D
authors.lastname: Chu
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
authors.forename: Svetlana S
authors.initials: SS
authors.lastname: Printsevskaya
authors.forename: Svetlana E
authors.initials: SE
authors.lastname: Solovieva
authors.forename: Evgenia N
authors.initials: EN
authors.lastname: Olsufyeva
authors.forename: Henry
authors.initials: H
authors.lastname: Heine
authors.forename: Julie
authors.initials: J
authors.lastname: Lovchik
authors.forename: C Richard
authors.initials: CR
authors.lastname: Lyons
mesh_terms: D000818:Animals; D000881:Anthrax / Q000401:mortality / Q000517:prevention & control; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001408:Bacillus anthracis / Q000187:drug effects*; D024881:Drug Resistance, Bacterial; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000401:mortality / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C523421:AN 0900; D000900:Anti-Bacterial Agents; D006020:Glycopeptides