Synthesis and structure-activity studies of novel homomorpholine oxazolidinone antibacterial agents.

A novel series of oxazolidinones were synthesized in which the morpholine C-ring of linezolid was replaced with homomorpholine. In addition to investigating the effect of a homomorpholine C-ring on antibacterial activity, the effect of des-, mono-, di-, and tri-fluoro substitution on the phenyl B-ring was investigated as well. Various C-5 functional groups were also examined, including acetamides and triazoles and carboxamides.

Antibacterial oxazolidinones possessing a novel C-5 side chain. (5R)-trans-3-[3-Fluoro-4- (1-oxotetrahydrothiopyran-4-yl)phenyl]-2- oxooxazolidine-5-carboxylic acid amide (PF-00422602), a new lead compound.

Oxazolidinones possessing a C-5 carboxamide functionality (reverse amides) represent a new series of compounds that block bacterial protein synthesis. These reverse amides also exhibited less potency against monoamine oxidase (MAO) enzymes and thus possess less potential for the side effects associated with MAO inhibition. The title compound (14) showed reduced in vivo myelotoxicity compared to linezolid in a 14-day safety study in rats, potent in vivo efficacy in murine systemic infection models, and excellent pharmacokinetic properties.

Effects of linezolid on staphylococcal adherence versus time of treatment.

Staphylococcus epidermidis has emerged as a major nosocomial pathogen that is often associated with infections of indwelling medical devices. Microbial adhesion to implanted foreign materials is a prerequisite for establishing infection. We studied the time-dependent anti-adhesion effects of linezolid and vancomycin on three S. epidermidis clinical isolates. Minimum inhibitory concentration (MIC) values were identical for both agents for all three isolates (2 mg/l). Bacterial suspensions were added to polystyrene wells and treated with 0.5-4 times the MIC of linezolid or vancomycin at 0, 2, 4 or 6 h post-inoculation. Supra-inhibitory (2 and 4 x MIC) and inhibitory (MIC) concentrations of linezolid demonstrated potent anti-adhesion activity following 2 and 4 h deferred treatments. Even at sub-inhibitory concentrations (0.5 x MIC), suppression of staphylococcal adherence to polystyrene was still evident in most cultures. Linezolid at two and four times the MIC also exerted significant inhibitory effects in cultures that had been treated with a 6-h delay. Supra-inhibitory and inhibitory concentrations of vancomycin administered 2 h post-infection appeared equally effective as linezolid. However, sub-inhibitory concentrations of vancomycin showed minimal or no activity against bacterial adhesion. When vancomycin treatments were delayed by 4 h, only concentrations above the MIC prevented adherence. Linezolid has promising in vitro anti-adhesion activity that merits further studies to determine its role in the management of foreign-body infections.

Efficacy of linezolid plus rifampin in an experimental model of methicillin-susceptible Staphylococcus aureus endocarditis.

The efficacy of linezolid, alone or in combination with rifampin, against methicillin-susceptible Staphylococcus aureus in rabbits with experimental endocarditis was investigated. Linezolid (50 or 75 mg/kg of body weight), rifampin, and linezolid (25, 50, or 75 mg/kg) plus rifampin produced statistically significant reductions in bacterial counts compared with those in untreated controls. Plasma or valvular vegetation levels of linezolid in the groups treated with the linezolid-rifampin combination were similar to those in the respective linezolid-only treatment groups. At therapeutic levels of linezolid, rifampin resistance was not observed. The results from this experimental model of endocarditis suggest that while rifampin did not provide synergy to the linezolid dosing, it did not antagonize the efficacy of linezolid.