In vitro activity of novel rifamycins against rifamycin-resistant Staphylococcus aureus.
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.
Murphy
Christopher K
CK
ActivBiotics, Inc., 110 Hartwell Avenue, Lexington, Massachusetts 02421, USA. cmurphy@activbiotics.com
Mullin
Steve
S
Osburne
Marcia S
MS
van Duzer
John
J
Siedlecki
Jim
J
Yu
Xiang
X
Kerstein
Kathy
K
Cynamon
Michael
M
Rothstein
David M
DM
D024881:Drug Resistance, Bacterial; D066298:In Vitro Techniques; D008968:Molecular Conformation; D017828:Rifabutin / Q000737:chemistry / Q000494:pharmacology*; D012293:Rifampin / Q000737:chemistry / Q000494:pharmacology*; D012294:Rifamycins / Q000737:chemistry / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics
D012294:Rifamycins; C068980:KRM 1648; D017828:Rifabutin; D012293:Rifampin