In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents

Abstract

Oxazolidinones make up a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. U-100592 (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]- phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and U-100766 (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]- 2-oxo-5-oxazolidinyl]methyl]-acetamide are novel oxazolidinone analogs from a directed chemical modification program. MICs were determined for a variety of bacterial clinical isolates; the respective MICs of U-100592 and U-100766 at which 90% of isolates are inhibited were as follows: methicillin-susceptible Staphylococcus aureus, 4 and 4 micrograms/ml; methicillin-resistant S. aureus, 4 and 4 micrograms/ml; methicillin-susceptible Staphylococcus epidermidis, 2 and 2 micrograms/ml; methicillin-resistant S. epidermidis, 1 and 2 micrograms/ml; Enterococcus faecalis, 2 and 4 micrograms/ml; Enterococcus faecium, 2 and 4 micrograms/ml; Streptococcus pyogenes, 1 and 2 micrograms/ml; Streptococcus pneumoniae, 0.50 and 1 microgram/ml; Corynebacterium spp., 0.50 and 0.50 micrograms/ml; Moraxella catarrhalis, 4 and 4 micrograms/ml; Listeria monocytogenes, 8 and 2 micrograms/ml; and Bacteroides fragilis, 16 and 4 micrograms/ml. Most strains of Mycobacterium tuberculosis and the gram-positive anaerobes were inhibited in the range of 0.50 to 2 micrograms/ml. Enterococcal strains resistant to vancomycin (VanA, VanB, and VanC resistance phenotypes), pneumococcal strains resistant to penicillin, and M. tuberculosis strains resistant to common antitubercular agents (isoniazid, streptomycin, rifampin, ethionamide, and ethambutol) were not cross-resistant to the oxazolidinones. The presence of 10, 20, and 40% pooled human serum did not affect the antibacterial activities of the oxazolidinones. Time-kill studies demonstrated a bacteriostatic effect of the analogs against staphylococci and enterococci but a bactericidal effect against streptococci. The spontaneous mutation frequencies of S. aureus ATCC 29213 were <3.8 x 10(-10) and <8 x 10(-11) for U-100592 and U-100766, respectively. Serial transfer of three staphylococcal and two enterococcal strains on drug gradient plates produced no evidence of rapid resistance development. Thus, these new oxazolidinone analogs demonstrated in vitro antibacterial activities against a variety of clinically important human pathogens.

Oxazolidinones: a novel class of antibiotics

“…A recent summary of the results obtained with linezolid and eperezolid together with the relevant literature is given in [7]. Linezolid and eperezolid are active against sensitive and multidrug-resistant Gram-positive organisms, such as Staphylococcus spp., including S. aureus und S. epidermidis, Streptococcus spp., including S. pneumoniae and S. pyogenes, Enterococcus spp., including E. faecalis and E. faecium, Corynebacterium spp., Mycobacterium spp., including M. tuberculosis, Actinomyces spp., Clostridium spp., Lactobacillus spp., Peptostreptococcus spp., Propionibacterium spp., Haemophilus influenzae, Listeria monocytogenes, Moraxella catarrhalis [18,19]. In addition, they show activity against a variety of anaerobic, Gram-negative bacteria such as Bacteroides spp., Bilophila wadworthia, Fusobacterium spp., Mobiluncus spp., Pre6otella spp., Porphyromonas asaccharolyticus, Veillonella alcalescens [19].…”

“…Oxazolidinones have been successfully used to inhibit bacterial strains which were resistant amongst others to methicillin, vancomycin, penicillin, rifampin and other antitubercular agents [7,18]. The lack of crossresistance with other, contemporary antibiotics is explained by the unique mechanism of action of the oxazolidinones.…”

Linezolid, Critical Characteristics

“…We felt this was particularly important with the staphylococci and their propensity for resistance development which is well known. More recently the novel use of a spiral gradient plating technique has resulted in the isolation of S. aureus isolates which are resistant to eperezolid and linezolid [7,9,11]. Over 20 serial transfers in a drug gradient were required to produce one resistant S. aureus with a MIC of 32 mg/l for eperezolid and which was cross-resistant with linezolid.…”

Efficacy and Safety of Linezolid in the Treatment of Skin and Soft Tissue Infections

“…It appears to act by inhibiting the initiation phase of protein synthesis, probably by binding to the 50S ribosomal subunit during the formation of the initiation complex [14,15,16]. Because of its unique mechanism of action, cross-resistance with other antimicrobial agents is difficult to develop [12,17].…”