The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria.
The oxazolidinones are one of the newest classes of antibiotics. They inhibit bacterial growth by interfering with protein synthesis. The mechanism of oxazolidinone action and the precise location of the drug binding site in the ribosome are unknown. We used a panel of photoreactive derivatives to identify the site of action of oxazolidinones in the ribosomes of bacterial and human cells. The in vivo crosslinking data were used to model the position of the oxazolidinone molecule within its binding site in the peptidyl transferase center (PTC). Oxazolidinones interact with the A site of the bacterial ribosome where they should interfere with the placement of the aminoacyl-tRNA. In human cells, oxazolidinones were crosslinked to rRNA in the PTC of mitochondrial, but not cytoplasmic, ribosomes. Interaction of oxazolidinones with the mitochondrial ribosomes provides a structural basis for the inhibition of mitochondrial protein synthesis, which is linked to clinical side effects associated with oxazolidinone therapy.
Leach
Karen L
KL
Pfizer Inc., 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Swaney
Steven M
SM
Colca
Jerry R
JR
McDonald
William G
WG
Blinn
James R
JR
Thomasco
Lisa M
LM
Gadwood
Robert C
RC
Shinabarger
Dean
D
Xiong
Liqun
L
Mankin
Alexander S
AS
D000081:Acetamides; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology; D004351:Drug Resistance / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D000069349:Linezolid; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D023303:Oxazolidinones / Q000737:chemistry / Q000494:pharmacology*; D010458:Peptidyl Transferases / Q000187:drug effects* / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000187:drug effects* / Q000378:metabolism; D012338:RNA, Ribosomal, 23S; D012346:RNA, Transfer, Amino Acyl / Q000037:antagonists & inhibitors / Q000378:metabolism; D012984:Software; D013194:Staining and Labeling; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology
D000081:Acetamides; D000890:Anti-Infective Agents; D003432:Cross-Linking Reagents; D023303:Oxazolidinones; D011500:Protein Synthesis Inhibitors; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D012338:RNA, Ribosomal, 23S; D012346:RNA, Transfer, Amino Acyl; D010458:Peptidyl Transferases; D000069349:Linezolid