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Article

Novel Semisynthetic Derivative of Antibiotic Eremomycin Active against Drug-Resistant Gram-Positive Pathogens Including Bacillus anthracis^†

Supporting Info

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, Julie Lovchik,^# and C. Richard Lyons^#

Anacor Pharmaceuticals, Inc., 1060 East Meadow Circle, Palo Alto, California 94303, Galileo Pharmaceuticals, Inc., 5301 Patrick Henry, Drive Santa Clara, California 95054, Gause Institute of New Antibiotics, Bolshaya Pirogovskaya 11, Moscow 119021, Russia, USAMRIID Bacteriology Division, 1425 Porter Street, Fort Detrick, Frederick, Maryland 21702, and University of New Mexico Health Sciences Center, BMSB G41, MSC10 5550, 1 University of New Mexico, Albuquerque, New Mexico, 87131

J. Med. Chem., 2007, 50 (15), pp 3681–3685

DOI: 10.1021/jm0700058

Publication Date (Web): July 3, 2007

†

Part of this work was presented at the annual 45^th ICAAC 2005, Washington (U.S.A.).

‡

Anacor Pharmaceuticals, Inc.

Galileo Pharmaceuticals, Inc.

To whom corresondence should be addressed. Tel.: 74952453753. Fax: 74952469980. E-mail: mnp@space.ru.

Gause Institute of New Antibiotics.

USAMRIID Bacteriology Division.

University of New Mexico.

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 μg/mL). It was distinguished by having a 2.8 h half-life (t_1/2) 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.

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Published In Issue July 26, 2007
Received January 3, 2007

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Article

Novel Semisynthetic Derivative of Antibiotic Eremomycin Active against Drug-Resistant Gram-Positive Pathogens Including Bacillus anthracis^†