| Reference | 1. Anaerobe. 1997 Oct;3(5):301-6.
<br>
In vitro activity of linezolid and eperezolid, two novel oxazolidinone
antimicrobial agents, against anaerobic bacteria.
<br>
Yagi BH(1), Zurenko GE.
<br>
Author information: <br>
(1)Pharmacia & Upjohn, Inc. Infectious Diseases Research, Kalamazoo, MI 49001,
USA.
<br>
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 </=0.25-1 microg/mL. Clostridial
species were generally susceptible to the oxazolidinones (MICs of </=0.25-8
microg/mL); however, seven strains of Clostridium difficile with linezolid MICs
of 16 microg/mL or greater were detected. Against the anaerobic Gram-negative
organisms, linezolid was more potent than 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 </=0.25-0.5 microg/mL). Overall, the oxazolidinones
demonstrated a significant level of activity against a number of
clinically-important anaerobic bacterial species. Linezolid may potentially
provide a broader spectrum of anaerobic coverage than eperezolid due to its
greater activity against Bacteroides species.
<br><br>
2. Antimicrob Agents Chemother. 1997 Oct;41(10):2127-31.
<br>
The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with
binding of chloramphenicol and lincomycin.
<br>
Lin AH(1), Murray RW, Vidmar TJ, Marotti KR.
<br>
Author information: <br>
(1)Molecular Biology Research, Pharmacia & Upjohn, Kalamazoo, Michigan 49007,
USA.
<br>
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.
<br><br>
3. Expert Opin Investig Drugs. 1997 Feb;6(2):151-8.
<br>
Oxazolidinone antibacterial agents: development of the clinical candidates
eperezolid and linezolid.
<br>
Zurenko GE(1), Ford CW, Hutchinson DK, Brickner SJ, Barbachyn MR.
<br>
Author information: <br>
(1)Pharmacia & Upjohn, Inc.,7000 Portage Road, Kalamazoo, MI 49001-0199, USA.
<br>
Antimicrobial resistance is a significant nosocomial problem and is of increasing
importance in community-acquired infections. One approach for overcoming
resistance is the discovery and development of agents with new mechanisms of
action. The oxazolidinones make up a relatively new class of antimicrobial agents
which possess a unique mechanism of bacterial protein synthesis inhibition.
Eperezolid and linezolid are two novel analogues that have demonstrated a variety
of positive attributes. These agents inhibit many clinically-significant
bacterial species both in vitro and in animal models of human infection.
Furthermore they have oral bioavailability, and are well tolerated in humans at
doses which produce plasma concentrations in excess of the levels predicted to be
necessary for efficacy. In this review, we discuss the key information from the
literature that supports the Phase II development of linezolid.
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