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Identification
Name Linezolid
Accession Number DB00601 (APRD01073, DB08769)
Type small molecule
Groups approved
Description

Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA). The drug works by inhibiting the initiation of bacterial protein synthesis.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • linezolid
Brand names
  • Linezlid
  • Zyvox
  • Zyvoxid
Brand name mixtures Not Available
Categories
  • Anti-Infective Agents
  • Protein Synthesis Inhibitors
  • Antibacterial Agents
CAS number 165800-03-3
Weight Average: 337.3461
Monoisotopic: 337.143784348
Chemical Formula C16H20FN3O4
InChI Key InChIKey=TYZROVQLWOKYKF-ZDUSSCGKSA-N
InChI
InChI=1S/C16H20FN3O4/c1-11(21)18-9-13-10-20(16(22)24-13)12-2-3-15(14(17)8-12)19-4-6-23-7-5-19/h2-3,8,13H,4-7,9-10H2,1H3,(H,18,21)/t13-/m0/s1
Plain Text
IUPAC Name
N-{[(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide
SMILES
CC(=O)NC[C@H]1CN(C(=O)O1)C1=CC(F)=C(C=C1)N1CCOCC1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carbamates and Derivatives
  • Benzene and Derivatives
  • Halobenzenes
  • Morpholines
  • Oxazolidinones
  • Anilines
Substructures
  • Carbamates and Derivatives
  • Amino Ketones
  • Aliphatic and Aryl Amines
  • Ethers
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Halobenzenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Morpholines
  • Oxazolidinones
  • Aryl Halides
  • Anilines
Pharmacology
Indication For the treatment of bacterial infections caused by susceptible strains of vancomycin resistant Enterococcus faecium, Staphylococcal aureus (methicillin resistant and susceptible strains), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae.
Pharmacodynamics Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Susceptible organisms include methicillin- and vancomycin-resistant staphylococci, vancomycin-resistant enterococci, penicillin-resistant pneumococci and anaerobes. Oxazolidinones inhibit protein synthesis by binding at the P site at the ribosomal 50S subunit. Resistance to other protein synthesis inhibitors does not affect oxazolidinone activity, however rare development of oxazolidinone resistance cases, associated with 23S rRNA alterations during treatment have been reported. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely.
Mechanism of action Linezolid is a synthetic antibacterial agent of the oxazolidinone class of antibiotics. It has in vitro activity against aerobic Gram positive bacteria, certain Gram negative bacteria and anaerobic microorganisms. It selectively inhibits bacterial protein synthesis through binding to sites on the bacterial ribosome and prevents the formation of a functional 70S-initiation complex. Specifically, linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains. Linezolid is also a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
Absorption Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%.
Volume of distribution
  • 40 to 50 L [healthy adult volunteers]
Protein binding 31%
Metabolism

Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite
Route of elimination Not Available
Half life 4.5-5.5 hours
Clearance Not Available
Toxicity Clinical signs of acute toxicity lead to decreased activity, ataxia, vomiting and tremors.
Affected organisms
  • Gram negative and gram positive bacteria
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pharmacia and upjohn co
Packagers
Dosage forms
Form Route Strength
Solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Zyvox 600 mg tablet 93.81 USD tablet
Zyvox 200 mg/100 ml iv soln 0.6 USD ml
Patents
Country Patent Number Approved Expires
United States 6514529 2001-09-15 2021-09-15
United States 5688792 1994-11-18 2014-11-18
Canada 2168560 2001-08-14 2014-08-16
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility 3 mg/mL PhysProp
logP 0.9 PhysProp
Predicted Properties
Property Value Source
water solubility 1.44e+00 g/l ALOGPS
logP 0.61 ALOGPS
logP 0.64 ChemAxon Molconvert
logS -2.37 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 71.11 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 84.47 ChemAxon Molconvert
polarizability 34.06 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Link
  2. Park IN, Hong SB, Oh YM, Kim MN, Lim CM, Lee SD, Koh Y, Kim WS, Kim DS, Kim WD, Shim TS: Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis. J Antimicrob Chemother. 2006 Sep;58(3):701-4. Epub 2006 Jul 19. Pubmed
External Links
Resource Link
KEGG Drug D00947 Link_out
KEGG Compound C08146 Link_out
PubChem Compound 441401 Link_out
PubChem Substance 46504452 Link_out
ChemSpider 390139 Link_out
BindingDB 50116067 Link_out
Therapeutic Targets Database DAP000398 Link_out
PharmGKB PA450233 Link_out
HET ZLD Link_out
Drug Product Database 2243684 Link_out
RxList http://www.rxlist.com/cgi/generic3/linezolid.htm Link_out
Drugs.com http://www.drugs.com/cdi/linezolid.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/zyv1556.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Linezolid Link_out
ATC Codes
  • J01XX08
AHFS Codes
  • 08:12.28.24
PDB Entries Not Available
FDA label show (106.1 KB)
MSDS show (43.7 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. 23S rRNA

Pharmacological action: yes
Actions: inhibitor

In prokaryotes, the 23S rRNA is part of the large subunit (the 50S) that joins with the 30S small subunit to create the functional 70S ribosome. The ribosome is comprised of 3 RNAs: the 23S, the 16S and the 5S ribosomal RNAs. The 23S and the 5S associate with their respective proteins to make up the large subunit of the ribosome, while the 16S RNA associates with its proteins to make up the small subunit.

Gene Sequence: FASTA

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Sinclair A, Arnold C, Woodford N: Rapid detection and estimation by pyrosequencing of 23S rRNA genes with a single nucleotide polymorphism conferring linezolid resistance in Enterococci. Antimicrob Agents Chemother. 2003 Nov;47(11):3620-2. Pubmed
  4. Meka VG, Pillai SK, Sakoulas G, Wennersten C, Venkataraman L, DeGirolami PC, Eliopoulos GM, Moellering RC Jr, Gold HS: Linezolid resistance in sequential Staphylococcus aureus isolates associated with a T2500A mutation in the 23S rRNA gene and loss of a single copy of rRNA. J Infect Dis. 2004 Jul 15;190(2):311-7. Epub 2004 Jun 9. Pubmed
  5. Zhu W, Tenover FC, Limor J, Lonsway D, Prince D, Dunne WM Jr, Patel JB: Use of pyrosequencing to identify point mutations in domain V of 23S rRNA genes of linezolid-resistant Staphylococcus aureus and Staphylococcus epidermidis. Eur J Clin Microbiol Infect Dis. 2007 Mar;26(3):161-5. Pubmed
  6. Colca JR, McDonald WG, Waldon DJ, Thomasco LM, Gadwood RC, Lund ET, Cavey GS, Mathews WR, Adams LD, Cecil ET, Pearson JD, Bock JH, Mott JE, Shinabarger DL, Xiong L, Mankin AS: Cross-linking in the living cell locates the site of action of oxazolidinone antibiotics. J Biol Chem. 2003 Jun 13;278(24):21972-9. Epub 2003 Apr 10. Pubmed
  7. Feng J, Lupien A, Gingras H, Wasserscheid J, Dewar K, Legare D, Ouellette M: Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance. Genome Res. 2009 Jul;19(7):1214-23. Epub 2009 Apr 6. Pubmed
Enzymes

1. Amine oxidase [flavin-containing] A

Actions: inhibitor

Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOA preferentially oxidizes biogenic amines such as 5-hydroxytryptamine (5-HT), norepinephrine and epinephrine

UniProt ID: P21397 Link_out
Gene: MAOA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Stevens DL, Dotter B, Madaras-Kelly K: A review of linezolid: the first oxazolidinone antibiotic. Expert Rev Anti Infect Ther. 2004 Feb;2(1):51-9. Pubmed
  2. Taylor JJ, Wilson JW, Estes LL: Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006 Jul 15;43(2):180-7. Epub 2006 Jun 9. Pubmed

2. Amine oxidase [flavin-containing] B

Actions: inhibitor

Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine

UniProt ID: P27338 Link_out
Gene: MAOB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Stevens DL, Dotter B, Madaras-Kelly K: A review of linezolid: the first oxazolidinone antibiotic. Expert Rev Anti Infect Ther. 2004 Feb;2(1):51-9. Pubmed
  2. Taylor JJ, Wilson JW, Estes LL: Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006 Jul 15;43(2):180-7. Epub 2006 Jun 9. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on October 11, 2011 16:55

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.