In vitro activity of novel rifamycins against rifamycin-resistant Staphylococcus aureus |
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Authors: | Murphy Christopher K Mullin Steve Osburne Marcia S van Duzer John Siedlecki Jim Yu Xiang Kerstein Kathy Cynamon Michael Rothstein David M |
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Affiliation: | ActivBiotics, Inc., 110 Hartwell Avenue, Lexington, Massachusetts 02421, USA. cmurphy@activbiotics.com |
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Abstract: | 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 microg/ml, in contrast to MICs of rifampin and rifalazil, which were 512 microg/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. |
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