ranbezolid and Staphylococcal-Infections

Silkworm (Bombyx mori) larvae were investigated as an alternative animal model for the efficacy testing of novel oxazolidinones. The minimal lethal dose (MLD) for Staphylococcus aureus was 1-5 x 10(7) CFU per larva, exhibiting more than 90% mortality within 2 to 4 days post-infection. Treatment with vancomycin, linezolid, and novel oxazolidinones (RBx 7644, RBx 8700, and RBx 2006171) showed survival in a dose-dependent manner. The antibacterial potential of RBx 7644 and RBx 8700 was compared with that of linezolid and that of vancomycin and the effective doses (ED)50 obtained in the silkworm model were 37.89, 24.96, 13.38, and 30.72 mg/kg body weight, respectively. The ED50 values showed a similar trend in a murine model of infection. Owing to the small size of the larvae, very small amounts of new chemical entities (NCEs) are required to test their in vivo efficacy in this model. Thus, the silkworm model may be used in the early stage of new discovery research.

Topics: Animals; Anti-Infective Agents; Bombyx; Disease Models, Animal; Furans; Humans; Larva; Methicillin Resistance; Mice; Oxazoles; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Novel oxazolidinones were synthesized containing a number of substituted five-membered heterocycles attached to the 'piperazinyl-phenyl-oxazolidinone' core of eperezolid. Further, the piperazine ring of the core was replaced by other diamino-heterocycles. These modifications led to several compounds with potent activity against a spectrum of resistant and susceptible gram-positive organisms, along with the identification of ranbezolid (RBx 7644) as a clinical candidate.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Furans; Gram-Positive Bacteria; Heterocyclic Compounds; Mice; Microbial Sensitivity Tests; Oxazoles; Oxazolidinones; Staphylococcal Infections; Structure-Activity Relationship

For 260 pneumococcal and 266 staphylococcal strains, ranbezolid MICs ranged from < or =0.06 to 4 micro g/ml. The MICs for pneumococci were similar irrespective of the strains' beta-lactam, macrolide, or quinolone susceptibilities, and ranbezolid MICs for coagulase-negative staphylococci were lower than those for Staphylococcus aureus. Ranbezolid was bacteriostatic against pneumococci. Ranbezolid MICs were similar to or lower than those of linezolid. Vancomycin and quinupristin-dalfopristin were also very active.

Topics: Anti-Bacterial Agents; Culture Media; Furans; Humans; Kinetics; Microbial Sensitivity Tests; Oxazoles; Pneumococcal Infections; Staphylococcal Infections; Staphylococcus; Streptococcus pneumoniae