Linezolid

Linezolid was introduced in 1996.Linezolid can be considered as the first member of the class of oxazolidinone antibiotics. Oxazolidinones was first introduced in 1978 for their effectiveness in the control of plant diseases. The US Food and Drug Administration approved Linezolid in 2000. Linezolid is an organofluorine compound that consists of 1,3-oxazolidin-2-one bearing an N-3-fluoro-4-(morpholin-4-yl)phenyl group as well as an acetamidomethyl group at position 5. Linezolid is an oxazolidinone, a member of morpholines, an organofluorine compound and a member of acetamides.

 Linezolid is an organofluorine compound with chemical name (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide and empirical formula of C16H20FN3O4.

Linezolid is a synthetic antibiotic, which is used for the treatment of infections caused by aerobic Gram-positive bacteria. Linezolid is an oxazolidinone antibiotic. 

It possesses bacteriostatic activity against enterococci and staphylococci but is bactericidal for most streptococcal strains. Linezolid exerts its antibacterial activity by inhibiting the initiation of bacterial protein synthesis, it binds to the 23S ribosomal RNA of the 50S subunit7, 8 and prevents the formation of the 70S initiation complex which is essential for bacterial reproduction. Linezolid use has become increasingly important for the treatment of multidrug-resistant infections caused by gram-positive microorganisms, e.g., methicillin resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE).

Mechanism of action of linezolid:

Linezolid is a synthetic antibiotic belonging to a new class of antimicrobials called the oxazolidinones. Linezolid disrupts bacterial growth by inhibiting the initiation process in protein synthesis on both the 30S, and 50S ribosomal subunits. 

Linezolid inhibits the formation of initiation complex, which can reduce the length of the developed peptide chains and decrease the rate of translation reaction (inhibitors (e.g., chloramphenicol [Chloromycetin], clindamycin [Cleocin], aminoglycosides, and macrolides).

The morpholino group in the first ring (from the left) and the fluoride atom in the second ring increase the activity of the compound. Analysis of high-resolution structures of linezolid showed that it binds to a deep cleft of 50S ribosomal subunit that is surrounded by 23S rRNA nucleotides. Mutation of 23S rRNA has been established as one of the linezolid resistance mechanisms.

Structure–activity relationship of linezolid:

The structure–activity relationship of oxazolidinones revealed that the N-aryl group and 5-S configuration are essential for the activity. The 5-acylaminomethyl group is responsible for the activity. The electron-withdrawing group in the aryl ring has been shown to increase the activity. 

Extra substituents on the aromatic ring do not affect the antibacterial activity but can change the solubility and pharmacokinetics. At pH 7.4, linezolid exists in an uncharged state. It is moderately water-soluble.

Some of the impurities of Linezolid are tabulated below.

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