Linezolid-induced inhibition of mitochondrial protein synthesis.
BACKGROUND
Linezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled.


METHODS
We studied mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, we evaluated mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo.


RESULTS
In the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal.


CONCLUSIONS
These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences. Prolonged courses of linezolid should be avoided if alternative treatment options are available.
De Vriese
An S
AS
Department of Internal Medicine, AZ Sint-Jan AV, Bruges, Belgium. an.devriese@azbrugge.be
Coster
Rudy Van
RV
Smet
Joel
J
Seneca
Sara
S
Lovering
Andrew
A
Van Haute
Lindsey L
LL
Vanopdenbosch
Ludo J
LJ
Martin
Jean-Jacques
JJ
Groote
Chantal Ceuterick-de
CC
Vandecasteele
Stefaan
S
Boelaert
Johan R
JR
D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D023303:Oxazolidinones / Q000494:pharmacology* / Q000627:therapeutic use*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy*
D000081:Acetamides; D000890:Anti-Infective Agents; D004272:DNA, Mitochondrial; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; D000069349:Linezolid; D012293:Rifampin