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Gary E Zurenko - One of the best experts on this subject based on the ideXlab platform.
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The discovery of linezolid, the first oxazolidinone antibacterial agent.
Current drug targets. Infectious disorders, 2001Co-Authors: Charles W. Ford, Gary E Zurenko, Michael R BarbachynAbstract:The emergence of new antibiotic-resistance in the significant Gram-positive pathogens in the last decade created a substantial medical need for new classes of antibacterial agents. Pharmacia Corporation scientists initiated a discovery research program in oxazolidinone chemistry and biology. Indanone-, tetralone-, and indoline-subunit oxazolidinones provided proof-of-concept interim improvements in antibacterial activity and safety SAR for the program. A method for enantiomeric enrichment of analogs was developed and intensive synthesis and evaluation efforts were undertaken with three oxazolidinone subclasses; the piperazine, indoline, and tropones. Members of the piperazinyl-phenyloxazolidinones possessed the most suitable chemical characteristics and biologic activity of the three subclasses. The monofluorophenyl congener Eperezolid and the morpholino analog linezolid emerged as the first clinical candidates from the piperazine oxazolidinones. Linezolid was selected for continued human clinical evaluation based upon its' superior pharmacokinetic profile. Microbiologic testing revealed that linezolid compared very favorably against comparator antibiotics in vitro and in animal infection models. Linezolid possessed a unique mechanism of action in that it inhibited functional 70S initiation complex formation and did not cross-react with existing bacterial resistance. Oral bioavailability in humans was determined to be 100% and twice daily dosing in humans resulted in blood levels which even at trough values were in excess of the MIC90 for significant Gram-positive pathogens. The preclinical promise of linezolid was realized in human clinical trials where linezolid was highly efficacious in the treatment of medically significant Gram-positive infections.
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piperazinyl oxazolidinone antibacterial agents containing a pyridine diazene or triazene heteroaromatic ring
Journal of Medicinal Chemistry, 1998Co-Authors: John A Tucker, Charles W. Ford, Steven J. Brickner, Debra A Allwine, Kevin C Grega, Michael R Barbachyn, Jennifer L Klock, Jenifer L Adamski, Douglas K Hutchinson, Gary E ZurenkoAbstract:Oxazolidinones are a novel class of synthetic antibacterial agents active against gram-positive organisms including methicillin-resistant Staphylococcus aureus as well as selected anaerobic organisms. Important representatives of this class include the morpholine derivative linezolid 2, which is currently in phase III clinical trials, and the piperazine derivative Eperezolid 3. As part of an investigation of the structure−activity relationships of structurally related oxazolidinones, we have prepared and evaluated the antibacterial properties of a series of piperazinyl oxazolidinones in which the distal nitrogen of the piperazinyl ring is substituted with a six-membered heteroaromatic ring. Compounds having MIC values ≤ 2 μg/mL vs selected gram-positive pathogens were discovered among each of the pyridine, pyridazine, and pyrimidine structural classes. Among these the cyanopyridine 17, the pyridazines 25 and 26, and the pyrimidine 31 exhibited in vivo potency vs S. aureus comparable to that of linezolid.
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Ribosomes from an Oxazolidinone-Resistant Mutant Confer Resistance to Eperezolid in a Staphylococcus aureus Cell-Free Transcription-Translation Assay
Antimicrobial agents and chemotherapy, 1998Co-Authors: Robert W. Murray, Gary E Zurenko, Ronda D. Schaadt, Keith R MarottiAbstract:Oxazolidinone-resistant mutants of Staphylococcus aureus, isolated with a spiral plating technique, had a 16-fold higher MIC (2 versus 32 μg/ml) of Eperezolid when compared to the parental sensitive strain. Eperezolid inhibited in vitro protein translation with 50% inhibitory concentrations of 30 μM for the oxazolidinone-sensitive S30 extract and 75 μM for the resistant extract. Experiments mixing various combinations of S100 and crude ribosome preparations from oxazolidinone-sensitive and -resistant S. aureus strains in a transcription-translation assay demonstrated that the resistant determinant resided within the ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less drug than ribosomes from the sensitive strain, indicating that the ribosome is the site of action for the oxazolidinones. These experiments demonstrate that an alteration of the ribosome is responsible for some or all of the oxazolidinone resistance observed in the S. aureus mutant.
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Ribosomes from an oxazolidinone-resistant mutant confer resistance to Eperezolid in a Staphylococcus aureus cell-free transcription-translation assay. Antimicrob Agents Chemother
1998Co-Authors: Robert W. Murray, Gary E Zurenko, Ronda D. Schaadt, R. MarottiAbstract:Oxazolidinone-resistant mutants of Staphylococcus aureus, isolated with a spiral plating technique, had a 16-fold higher MIC (2 versus 32 mg/ml) of Eperezolid when compared to the parental sensitive strain. Eperezolid inhibited in vitro protein translation with 50 % inhibitory concentrations of 30 mM for the oxazolidinone-sen-sitive S30 extract and 75 mM for the resistant extract. Experiments mixing various combinations of S100 and crude ribosome preparations from oxazolidinone-sensitive and-resistant S. aureus strains in a transcription-translation assay demonstrated that the resistant determinant resided within the ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less drug than ribosomes from the sensitive strain, indicating that the ribosome is the site of action for the oxazolidinones. These experiments demonstrate that an alteration of the ribosome is responsible for some or all of the oxazolidinone resistance observed in the S. aureus mutant. Oxazolidinones represent a new class of antimicrobial com-pounds that act by inhibiting protein synthesis (1, 2, 4–6, 8, 9, 14, 16a). They are potent antibacterial agents active against a wide variety of gram-positive organisms, including methicillin-resistant staphylococci, and show no cross-resistance with other antibiotics (1, 3, 4, 7, 17, 21). Previous studies hav
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in vitroactivity of linezolid and Eperezolid two novel oxazolidinone antimicrobial agents against anaerobic bacteria
Anaerobe, 1997Co-Authors: Betty H Yagi, Gary E ZurenkoAbstract:Linezolid (formerly U-100766) and Eperezolid (formerly U-100592) are novel oxazolidinone antimicrobial agents that are active against multi-drug-resistant staphylococci, streptococci, enterococci, corynebacteria, and mycobacteria. Preliminary studies also demonstrated that the compounds inhibited some test strains of anaerobic bacteria. Therefore, we extended the in vitro evaluation of these agents to include a total of 54 different anaerobic species. Minimal inhibitory concentration (MIC) values were determined using a standard agar dilution method for 143 anaerobic bacterial isolates. Eperezolid and linezolid demonstrated potent activity against the anaerobic Gram-positive organisms with most MIC values in the range of 0.25-4 microg/mL. Viridans streptococci demonstrated MICs of 1-2 microg/mL; Peptostreptococcus species and Propionibacterium species were inhibited by Eperezolid, especially for Bacteroides species. Linezolid inhibited most bacteroides in the range of 2-8 microg/mL, while Eperezolid was generally two- to eight-fold less active. Linezolid and Eperezolid both demonstrated potent activity against Fusobacterium species,Mobiluncus species,Prevotella intermedia, and Porphyromonas asaccharolytica (MICs of Eperezolid due to its greater activity against Bacteroides species.
Michael J. Rybak - One of the best experts on this subject based on the ideXlab platform.
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comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds Eperezolid pnu 100592 and linezolid pnu 100766 versus vancomycin against staphylococcus aureus coagulase negative staphylococci enterococcus faecalis and entero
Antimicrobial Agents and Chemotherapy, 1998Co-Authors: Michael J. Rybak, Diane M Cappelletty, Tabitha Moldovan, Jeffrey R Aeschlimann, Glenn W KaatzAbstract:The activities of the oxazolidinone antibacterial agents Eperezolid (PNU-100592) and linezolid (PNU-100766) were compared with that of vancomycin against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (n = 200), coagulase-negative staphylococci (n = 100), and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium (n = 50). Eperezolid and linezolid demonstrated good in vitro inhibitory activity, regardless of methicillin susceptibility for staphylococci (MIC at which 90% of the isolates are inhibited [MIC90] range, 1 to 4 microg/ml) or vancomycin susceptibility for enterococci (MIC90 range, 1 to 4 microg/ml). In time-kill studies, Eperezolid and linezolid were bacteriostatic in action. A postantibiotic effect of 0.8+/-0.5 h was demonstrated for both Eperezolid and linezolid against S. aureus, S. epidermidis, E. faecalis, and E. faecium.
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The pharmacologic and bacteriologic properties of oxazolidinones, a new class of synthetic antimicrobials.
Pharmacotherapy, 1998Co-Authors: Linda D. Dresser, Michael J. RybakAbstract:The oxazolidinones are a new synthetic class of antimicrobials structurally unrelated to any agent presently marketed. Data pertaining to these compounds, with respect to their pharmacology, pharmacokinetics, pharmacodynamics, mechanism of action, and bacteriologic activity, focusing on the analogs linezolid (PNU 100766) and Eperezolid (PNU 100592), were retrieved by MEDLINE search and review of relevant abstracts presented at recent clinical conferences. Since the drugs are still investigational, we obtained in vitro and animal data as well as available human studies. The oxazolidinones have bacteriostatic activity against a number of important pathogens including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci. They appear to be efficacious and well tolerated both orally and parenterally. Their role remains to be elucidated by clinical trials.
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In vitro activities of an investigational quinolone, glycylcycline, glycopeptide, streptogramin, and oxazolidinone tested alone and in combinations against vancomycin-resistant Enterococcus faecium.
Antimicrobial Agents and Chemotherapy, 1997Co-Authors: Renee Claude Mercier, Scott R. Penzak, Michael J. RybakAbstract:We evaluated the in vitro activities of clinafloxacin, CL331,002, LY333328, quinupristin dalfopristin, and Eperezolid (formerly known as U-100,592) against four strains of enterococci. All regimens tested resulted in the growth inhibition of each isolate. Against the three clinafloxacin-susceptible strains, clinafloxacin tested alone was the most active treatment, decreasing the bacterial inoculum by more than 3 log10 CFU/ml after 24 h in time-kill curve studies.
Keith R Marotti - One of the best experts on this subject based on the ideXlab platform.
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Ribosomes from an Oxazolidinone-Resistant Mutant Confer Resistance to Eperezolid in a Staphylococcus aureus Cell-Free Transcription-Translation Assay
Antimicrobial agents and chemotherapy, 1998Co-Authors: Robert W. Murray, Gary E Zurenko, Ronda D. Schaadt, Keith R MarottiAbstract:Oxazolidinone-resistant mutants of Staphylococcus aureus, isolated with a spiral plating technique, had a 16-fold higher MIC (2 versus 32 μg/ml) of Eperezolid when compared to the parental sensitive strain. Eperezolid inhibited in vitro protein translation with 50% inhibitory concentrations of 30 μM for the oxazolidinone-sensitive S30 extract and 75 μM for the resistant extract. Experiments mixing various combinations of S100 and crude ribosome preparations from oxazolidinone-sensitive and -resistant S. aureus strains in a transcription-translation assay demonstrated that the resistant determinant resided within the ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less drug than ribosomes from the sensitive strain, indicating that the ribosome is the site of action for the oxazolidinones. These experiments demonstrate that an alteration of the ribosome is responsible for some or all of the oxazolidinone resistance observed in the S. aureus mutant.
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the oxazolidinone Eperezolid binds to the 50s ribosomal subunit and competes with binding of chloramphenicol and lincomycin
Antimicrobial Agents and Chemotherapy, 1997Co-Authors: Alice H Lin, R W Murray, T J Vidmar, Keith R MarottiAbstract:The oxazolidinones are a novel class of antibiotics that act by inhibiting protein synthesis. It as been reported that the drug exerts its primary activity on the initiation phase of translation. In order to study the possibility of direct interaction between the drug and the ribosome, we have developed a binding assay using 14C-labelled Eperezolid (PNU-100592; formerly U-100592). Eperezolid binds specifically to the 50S ribosomal subunit of Escherichia coli. The specific binding of Eperezolid is dose dependent and is proportional to the ribosome concentrations. Scatchard analysis of the binding data reveals that the dissociation constant (Kd) is about 20 microM. The binding of Eperezolid to the ribosome is competitively inhibited by chloramphenicol and lincomycin. However, unlike chloramphenicol and lincomycin, Eperezolid does not inhibit the puromycin reaction, indicating that the oxazolidinones have no effect on peptidyl transferase. In addition, whereas lincomycin and, to some extent, chloramphenicol inhibit translation termination, Eperezolid has no effect. Therefore, we conclude that the oxazolidinones inhibit protein synthesis by binding to the 50S ribosomal subunit at a site close to the site(s) to which chloramphenicol and lincomycin bind but that the oxazolidinones are mechanistically distinct from these two antibiotics.
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Mechanism of Action of Oxazolidinones: Effects of Linezolid and Eperezolid on Translation Reactions
Antimicrobial agents and chemotherapy, 1997Co-Authors: Dean L. Shinabarger, Alice H Lin, Keith R Marotti, Steve M. Swaney, Robert W. Murray, Earline P. Melchior, Donna S. Dunyak, William F. Demyan, Jerry M. BuysseAbstract:The oxazolidinones are a new class of synthetic antibiotics with good activity against gram-positive pathogenic bacteria. Experiments with a susceptible Escherichia coli strain, UC6782, demonstrated that in vivo protein synthesis was inhibited by both Eperezolid (formerly U-100592) and linezolid (formerly U-100766). Both linezolid and Eperezolid were potent inhibitors of cell-free transcription-translation in E. coli, exhibiting 50% inhibitory concentrations (IC50s) of 1.8 and 2.5 microM, respectively. The ability to demonstrate inhibition of in vitro translation directed by phage MS2 RNA was greatly dependent upon the amount of RNA added to the assay. For Eperezolid, 128 microg of RNA per ml produced an IC50 of 50 microM whereas a concentration of 32 microg/ml yielded an IC50 of 20 microM. Investigating lower RNA template concentrations in linezolid inhibition experiments revealed that 32 and 8 microg of MS2 phage RNA per ml produced IC50s of 24 and 15 microM, respectively. This phenomenon was shared by the translation initiation inhibitor kasugamycin but not by streptomycin. Neither oxazolidinone inhibited the formation of N-formylmethionyl-tRNA, elongation, or termination reactions of bacterial translation. The oxazolidinones appear to inhibit bacterial translation at the initiation phase of protein synthesis.
Ronda D. Schaadt - One of the best experts on this subject based on the ideXlab platform.
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Carbon-carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria.
Bioorganic & medicinal chemistry, 2001Co-Authors: Chi Sing Lee, Charles W. Ford, Debra A Allwine, Kevin C Grega, Michael R Barbachyn, Lester A. Dolak, Randy M. Jensen, Eric P. Seest, Judith C. Hamel, Ronda D. SchaadtAbstract:Abstract In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon–carbon linked pyrazolylphenyl analogues has been prepared. The α- N -substituted methyl pyrazole ( 10 α) in the C3-linked series exhibited very good Gram-positive activity with MICs ≤0.5–1 μg/mL and moderate Gram-negative activity with MICs=2–8 μg/mL against Haemophilus influenzae and Moraxella catarrhalis . This analogue was also found to have potent in vivo activity with an ED 50 =1.9 mg/kg. β-Substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10 α. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than Eperezolid, linezolid and vancomycin. The thioamide of the N -cyanomethyl pyrazole analogue ( 34 ) exhibited an exceptional in vitro activity with MICs of ≤ 0.06–0.25 μg/mL against Gram-positive pathogens and with MICs of 1 μg/mL against fastidious Gram-negative pathogens.
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Ribosomes from an Oxazolidinone-Resistant Mutant Confer Resistance to Eperezolid in a Staphylococcus aureus Cell-Free Transcription-Translation Assay
Antimicrobial agents and chemotherapy, 1998Co-Authors: Robert W. Murray, Gary E Zurenko, Ronda D. Schaadt, Keith R MarottiAbstract:Oxazolidinone-resistant mutants of Staphylococcus aureus, isolated with a spiral plating technique, had a 16-fold higher MIC (2 versus 32 μg/ml) of Eperezolid when compared to the parental sensitive strain. Eperezolid inhibited in vitro protein translation with 50% inhibitory concentrations of 30 μM for the oxazolidinone-sensitive S30 extract and 75 μM for the resistant extract. Experiments mixing various combinations of S100 and crude ribosome preparations from oxazolidinone-sensitive and -resistant S. aureus strains in a transcription-translation assay demonstrated that the resistant determinant resided within the ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less drug than ribosomes from the sensitive strain, indicating that the ribosome is the site of action for the oxazolidinones. These experiments demonstrate that an alteration of the ribosome is responsible for some or all of the oxazolidinone resistance observed in the S. aureus mutant.
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Ribosomes from an oxazolidinone-resistant mutant confer resistance to Eperezolid in a Staphylococcus aureus cell-free transcription-translation assay. Antimicrob Agents Chemother
1998Co-Authors: Robert W. Murray, Gary E Zurenko, Ronda D. Schaadt, R. MarottiAbstract:Oxazolidinone-resistant mutants of Staphylococcus aureus, isolated with a spiral plating technique, had a 16-fold higher MIC (2 versus 32 mg/ml) of Eperezolid when compared to the parental sensitive strain. Eperezolid inhibited in vitro protein translation with 50 % inhibitory concentrations of 30 mM for the oxazolidinone-sen-sitive S30 extract and 75 mM for the resistant extract. Experiments mixing various combinations of S100 and crude ribosome preparations from oxazolidinone-sensitive and-resistant S. aureus strains in a transcription-translation assay demonstrated that the resistant determinant resided within the ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less drug than ribosomes from the sensitive strain, indicating that the ribosome is the site of action for the oxazolidinones. These experiments demonstrate that an alteration of the ribosome is responsible for some or all of the oxazolidinone resistance observed in the S. aureus mutant. Oxazolidinones represent a new class of antimicrobial com-pounds that act by inhibiting protein synthesis (1, 2, 4–6, 8, 9, 14, 16a). They are potent antibacterial agents active against a wide variety of gram-positive organisms, including methicillin-resistant staphylococci, and show no cross-resistance with other antibiotics (1, 3, 4, 7, 17, 21). Previous studies hav
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Serum inhibitory titers and serum bactericidal titers for human subjects receiving multiple doses of the antibacterial oxazolidinones Eperezolid and linezolid.
Diagnostic microbiology and infectious disease, 1997Co-Authors: Ronda D. Schaadt, Donald H. Batts, Peter T. Daley-yates, Steven D. Pawsey, Dennis J. Stalker, Gary E ZurenkoAbstract:In Phase I trials subjects received multiple doses of Eperezolid (PNU-100592; formerly U-100592) and linezolid (PNU-100766; formerly U-100766), and steady-state samples were drawn at the projected peak and trough timepoints. Serum inhibitory titer and serum bactericidal titer values were determined using single strains of Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae. Serum inhibitory titer values generally correlated with drug concentration in serum and inherent organism susceptibility. Against S. aureus and E. faecalis sera from patients dosed with either drug were generally inhibitory at the peak timepoint, but at trough only linezolid exhibited a persistent effect. No bactericidal activity was seen for either drug against S. aureus or E. faecalis. The sera from patients dosed with either drug exhibited inhibition of S. pneumoniae at peak and trough. Bactericidal activity was seen against S. pneumoniae for both drugs at peak time and at trough for many of the sera for patients on the higher dose regimens. The results demonstrated that the sera from most human subjects dosed with Eperezolid or linezolid were inhibitory to S. aureus and E. faecalis and S. pneumoniae and that many of the samples exhibited bactericidal activity for S. pneumoniae.
Robert W. Murray - One of the best experts on this subject based on the ideXlab platform.
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Ribosomes from an Oxazolidinone-Resistant Mutant Confer Resistance to Eperezolid in a Staphylococcus aureus Cell-Free Transcription-Translation Assay
Antimicrobial agents and chemotherapy, 1998Co-Authors: Robert W. Murray, Gary E Zurenko, Ronda D. Schaadt, Keith R MarottiAbstract:Oxazolidinone-resistant mutants of Staphylococcus aureus, isolated with a spiral plating technique, had a 16-fold higher MIC (2 versus 32 μg/ml) of Eperezolid when compared to the parental sensitive strain. Eperezolid inhibited in vitro protein translation with 50% inhibitory concentrations of 30 μM for the oxazolidinone-sensitive S30 extract and 75 μM for the resistant extract. Experiments mixing various combinations of S100 and crude ribosome preparations from oxazolidinone-sensitive and -resistant S. aureus strains in a transcription-translation assay demonstrated that the resistant determinant resided within the ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less drug than ribosomes from the sensitive strain, indicating that the ribosome is the site of action for the oxazolidinones. These experiments demonstrate that an alteration of the ribosome is responsible for some or all of the oxazolidinone resistance observed in the S. aureus mutant.
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Ribosomes from an oxazolidinone-resistant mutant confer resistance to Eperezolid in a Staphylococcus aureus cell-free transcription-translation assay. Antimicrob Agents Chemother
1998Co-Authors: Robert W. Murray, Gary E Zurenko, Ronda D. Schaadt, R. MarottiAbstract:Oxazolidinone-resistant mutants of Staphylococcus aureus, isolated with a spiral plating technique, had a 16-fold higher MIC (2 versus 32 mg/ml) of Eperezolid when compared to the parental sensitive strain. Eperezolid inhibited in vitro protein translation with 50 % inhibitory concentrations of 30 mM for the oxazolidinone-sen-sitive S30 extract and 75 mM for the resistant extract. Experiments mixing various combinations of S100 and crude ribosome preparations from oxazolidinone-sensitive and-resistant S. aureus strains in a transcription-translation assay demonstrated that the resistant determinant resided within the ribosomal fraction. Ribosomes from the oxazolidinone-resistant strain bound less drug than ribosomes from the sensitive strain, indicating that the ribosome is the site of action for the oxazolidinones. These experiments demonstrate that an alteration of the ribosome is responsible for some or all of the oxazolidinone resistance observed in the S. aureus mutant. Oxazolidinones represent a new class of antimicrobial com-pounds that act by inhibiting protein synthesis (1, 2, 4–6, 8, 9, 14, 16a). They are potent antibacterial agents active against a wide variety of gram-positive organisms, including methicillin-resistant staphylococci, and show no cross-resistance with other antibiotics (1, 3, 4, 7, 17, 21). Previous studies hav
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Mechanism of Action of Oxazolidinones: Effects of Linezolid and Eperezolid on Translation Reactions
Antimicrobial agents and chemotherapy, 1997Co-Authors: Dean L. Shinabarger, Alice H Lin, Keith R Marotti, Steve M. Swaney, Robert W. Murray, Earline P. Melchior, Donna S. Dunyak, William F. Demyan, Jerry M. BuysseAbstract:The oxazolidinones are a new class of synthetic antibiotics with good activity against gram-positive pathogenic bacteria. Experiments with a susceptible Escherichia coli strain, UC6782, demonstrated that in vivo protein synthesis was inhibited by both Eperezolid (formerly U-100592) and linezolid (formerly U-100766). Both linezolid and Eperezolid were potent inhibitors of cell-free transcription-translation in E. coli, exhibiting 50% inhibitory concentrations (IC50s) of 1.8 and 2.5 microM, respectively. The ability to demonstrate inhibition of in vitro translation directed by phage MS2 RNA was greatly dependent upon the amount of RNA added to the assay. For Eperezolid, 128 microg of RNA per ml produced an IC50 of 50 microM whereas a concentration of 32 microg/ml yielded an IC50 of 20 microM. Investigating lower RNA template concentrations in linezolid inhibition experiments revealed that 32 and 8 microg of MS2 phage RNA per ml produced IC50s of 24 and 15 microM, respectively. This phenomenon was shared by the translation initiation inhibitor kasugamycin but not by streptomycin. Neither oxazolidinone inhibited the formation of N-formylmethionyl-tRNA, elongation, or termination reactions of bacterial translation. The oxazolidinones appear to inhibit bacterial translation at the initiation phase of protein synthesis.