The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria

Karen L Leach; Steven M Swaney; Jerry R Colca; William G McDonald; James R Blinn; Lisa M Thomasco; Robert C Gadwood; Dean Shinabarger; Liqun Xiong; Alexander S Mankin

doi:10.1016/j.molcel.2007.04.005

The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria

Mol Cell. 2007 May 11;26(3):393-402. doi: 10.1016/j.molcel.2007.04.005.

Authors

Karen L Leach¹, Steven M Swaney, Jerry R Colca, William G McDonald, James R Blinn, Lisa M Thomasco, Robert C Gadwood, Dean Shinabarger, Liqun Xiong, Alexander S Mankin

Affiliation

¹ Pfizer Inc., 2800 Plymouth Road, Ann Arbor, MI 48105, USA.

PMID: 17499045
DOI: 10.1016/j.molcel.2007.04.005

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides
Anti-Infective Agents / chemistry
Anti-Infective Agents / pharmacology
Binding Sites / drug effects
Cross-Linking Reagents / chemistry
Cross-Linking Reagents / pharmacology
Cytoplasm / drug effects
Cytoplasm / enzymology
Drug Resistance / genetics
Escherichia coli / drug effects
Escherichia coli / enzymology
Humans
Linezolid
Mitochondria / drug effects*
Mitochondria / enzymology
Models, Molecular
Molecular Structure
Mutation / genetics
Oxazolidinones / chemistry
Oxazolidinones / pharmacology*
Peptidyl Transferases / drug effects*
Peptidyl Transferases / metabolism
Protein Synthesis Inhibitors / chemistry
Protein Synthesis Inhibitors / pharmacology*
RNA, Bacterial / genetics
RNA, Bacterial / metabolism
RNA, Ribosomal / drug effects*
RNA, Ribosomal / metabolism
RNA, Ribosomal, 23S
RNA, Transfer, Amino Acyl / antagonists & inhibitors
RNA, Transfer, Amino Acyl / metabolism
Software*
Staining and Labeling
Staphylococcus aureus / drug effects
Staphylococcus aureus / enzymology

Substances

Acetamides
Anti-Infective Agents
Cross-Linking Reagents
Oxazolidinones
Protein Synthesis Inhibitors
RNA, Bacterial
RNA, Ribosomal
RNA, Ribosomal, 23S
RNA, Transfer, Amino Acyl
Peptidyl Transferases
Linezolid