Linezolid Mechanism of Action and Antimicrobial Spectrum
Mechanism of Action
Linezolid inhibits bacterial protein synthesis by binding to the 23S ribosomal RNA of the 50S ribosomal subunit, preventing formation of the functional 70S initiation complex required for bacterial translation. 1
Linezolid binds to a deep cleft of the 50S ribosomal subunit surrounded by 23S rRNA nucleotides, blocking the initiation step of protein synthesis through a unique mechanism distinct from other protein synthesis inhibitors 2, 3
Unlike other antibiotics that block polypeptide extension or cause mRNA misreading, linezolid specifically prevents the formation of the initiation complex, which also reduces peptide chain length and decreases translation elongation rates 2, 3
This novel mechanism of action means cross-resistance with other antibiotic classes (including other protein synthesis inhibitors) is unlikely 1, 4
Linezolid also specifically inhibits 50S ribosomal subunit formation itself in bacterial cells, with equivalent potency to its translational inhibition (IC50 of 0.6 μg/ml for 50S synthesis versus 0.3 μg/ml for protein synthesis) 5
Antimicrobial Spectrum
Linezolid demonstrates potent activity against aerobic gram-positive bacteria, particularly drug-resistant strains, while remaining inactive against most gram-negative organisms due to endogenous efflux mechanisms. 1, 3
Gram-Positive Coverage (Primary Spectrum)
FDA-approved indications include: vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae (including multi-drug resistant isolates), Streptococcus pyogenes, and Streptococcus agalactiae 1
MIC values range from 0.5 to 4 mg/L for streptococci, enterococci, and staphylococci, with narrow and unimodal susceptibility distributions 3
Full activity is retained against gram-positive cocci resistant to other antibiotics, including methicillin-resistant staphylococci and vancomycin-resistant enterococci 3
Bacteriostatic vs. Bactericidal Activity
Linezolid is bacteriostatic against enterococci and staphylococci but bactericidal against most streptococcal strains 1, 4
The Infectious Diseases Society of America notes this bacteriostatic nature against enterococci is a consideration in serious infections like endocarditis, where combination therapy or alternative agents may be needed in immunocompromised patients or deep-seated infections 6
Bactericidal activity has also been demonstrated against some strains of Bacteroides fragilis and Clostridium perfringens 4
Limited Gram-Negative and Anaerobic Activity
MICs are 4-8 mg/L for Moraxella, Pasteurella, and Bacteroides species 3
Most gram-negative bacteria are resistant due to endogenous efflux activity 3
Anaerobes including Clostridium spp., Peptostreptococcus spp., and Prevotella spp. are susceptible 4
Resistance Mechanisms
Resistance to linezolid occurs through point mutations in the 23S rRNA at position 2576 (substitution of thymine for guanine), though resistance develops infrequently at rates of 1 × 10⁻⁹ to 1 × 10⁻¹¹ in vitro. 1, 3
Resistance has been documented in clinical use, particularly in E. faecium infections (6 patients in clinical trials, 8 in compassionate use programs) and rarely in MRSA 1
Risk factors for resistance development include unremoved prosthetic devices, undrained abscesses, protracted therapy, and underdosing 3
Mutations in ribosomal proteins uL3 and uL4 are increasingly associated with linezolid resistance, though these proteins are located further from the drug binding site 2
Nosocomial spread of vancomycin- and linezolid-resistant E. faecium has been reported, emphasizing the importance of infection control policies when resistant organisms are encountered 1