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Antimicrobial Agents and Chemotherapy, March 2006, p. 827-834, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.827-834.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Novel Rifamycins against Rifamycin-Resistant Staphylococcus aureus

Christopher K. Murphy,1* Steve Mullin,1,{dagger} Marcia S. Osburne,1,§ John van Duzer,1 Jim Siedlecki,1 Xiang Yu,1,{ddagger} Kathy Kerstein,2 Michael Cynamon,3 and David M. Rothstein1

ActivBiotics, Inc., Lexington, Massachusetts 02421,1 Tufts University School of Medicine, 136 Harrison Ave., Boston, Massachusetts 02111,2 Veterans Affairs Medical Center and State University of New York, Upstate Medical University, 800 Irving Ave., Syracuse, New York 132103

Received 26 July 2005/ Returned for modification 30 October 2005/ Accepted 12 December 2005

We describe novel rifamycin derivatives (new chemical entities [NCEs]) that retain significant activity against a comprehensive collection of Staphylococcus aureus strains that are resistant to rifamycins. This collection of resistant strains contains 21 of the 26 known single-amino-acid alterations in RpoB, the target of rifamycins. Some NCEs also demonstrated a lower frequency of resistance development than rifampin and rifalazil in S. aureus as measured in a resistance emergence test. When assayed for activity against the strongest rifamycin-resistant mutants, several NCEs had MICs of 2 µg/ml, in contrast to MICs of rifampin and rifalazil, which were 512 µg/ml for the same strains. The properties of these NCEs therefore demonstrate a significant improvement over those of earlier rifamycins, which have been limited primarily to combination therapy due to resistance development, and suggest a potential use of these NCEs for monotherapy in several clinical indications.

* Corresponding author. Mailing address: ActivBiotics, Inc., 110 Hartwell Avenue, Lexington, MA 02421. Phone: (781) 372-4821. Fax: (781) 274-9129. E-mail: cmurphy{at}activbiotics.com.

{dagger} Present address: Novartis Institutes for Biomedical Research, Inc., Infectious Disease, 100 Technology Sq., Cambridge, MA 02139.

§ Present address: Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 15 Vassar St., Cambridge, MA 02139.

{ddagger} Present address: Predix Pharmaceuticals, Inc., 4 Maguire Rd., Lexington, MA 02421.

Antimicrobial Agents and Chemotherapy, March 2006, p. 827-834, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.827-834.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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