Novel Semisynthetic Derivative of Antibiotic Eremomycin Active against Drug-Resistant Gram-Positive Pathogens Including Bacillus anthracis
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- 作者：Kirk R. Maples ; Conrad Wheeler ; Emily Ip ; Jacob J. Plattner ; Daniel Chu ; Yong-Kang Zhang ; Maria N. Preobrazhenskaya ; Svetlana S. Printsevskaya ; Svetlana E. Solovieva ; Evgenia N. Olsufyeva ; Henry Heine
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：July 26, 2007
- 年：2007
- 卷：50
- 期：15
- 页码：3681 - 3685
- 全文大小：69K
- 年卷期：v.50,no.15(July 26, 2007)
- ISSN：1520-4804
文摘
Five adamantyl-containing carboxamides of eremomycin or vancomycin were synthesized and theirantibacterial 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 activecompound and showed high activity against several Gram-positive pathogens: vancomycin-susceptiblestaphylococci 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 
g/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 Staphylococcusaureus in mice (iv) and provided complete protection against a lethal intravenous challenge with vegetativeB. anthracis bacilli and also in a murine pulmonary anthrax model in which mice were challenged withBacillus anthracis spores.
g/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 Staphylococcusaureus in mice (iv) and provided complete protection against a lethal intravenous challenge with vegetativeB. anthracis bacilli and also in a murine pulmonary anthrax model in which mice were challenged withBacillus anthracis spores.