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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, Marcia S. Osburne,^1, John van Duzer,¹ Jim Siedlecki,¹ Xiang Yu,^1, 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.

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.

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

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