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TitleContext-specific inhibition of mitochondrial ribosomes by phenicol and oxazolidinone antibiotics.
Journal, issue, pagesNucleic Acids Res, Vol. 53, Issue 3, Year 2025
Publish dateJan 24, 2025
AuthorsBrianna Bibel / Tushar Raskar / Mary Couvillion / Muhoon Lee / Jordan I Kleinman / Nono Takeuchi-Tomita / L Stirling Churchman / James S Fraser / Danica Galonić Fujimori /
PubMed AbstractThe antibiotics chloramphenicol (CHL) and oxazolidinones, including linezolid (LZD), are known to inhibit mitochondrial translation. This can result in serious, potentially deadly, side effects when ...The antibiotics chloramphenicol (CHL) and oxazolidinones, including linezolid (LZD), are known to inhibit mitochondrial translation. This can result in serious, potentially deadly, side effects when used therapeutically. Although the mechanism by which CHL and LZD inhibit bacterial ribosomes has been elucidated in detail, their mechanism of action against mitochondrial ribosomes has yet to be explored. CHL and oxazolidinones bind to the ribosomal peptidyl transfer center (PTC) of the bacterial ribosome and prevent incorporation of incoming amino acids under specific sequence contexts, causing ribosomes to stall only at certain sequences. Through mitoribosome profiling, we show that inhibition of mitochondrial ribosomes is similarly context-specific-CHL and LZD lead to mitoribosome stalling primarily when there is an alanine, serine, or threonine in the penultimate position of the nascent peptide chain. We further validate context-specific stalling through in vitro translation assays. A high-resolution cryo-electron microscopy structure of LZD bound to the PTC of the human mitoribosome shows extensive similarity to the mode of bacterial inhibition and also suggests potential avenues for altering selectivity. Our findings could help inform the rational development of future, less mitotoxic, antibiotics, which are critically needed in the current era of increasing antimicrobial resistance.
External linksNucleic Acids Res / PubMed:39907106 / PubMed Central
MethodsEM (single particle)
Resolution2.62 Å
Structure data

45757

9cn3

EMDB-45757, PDB-9cn3:
Human 39S mitoribosome in complex with antibiotic Linezolid
Method: EM (single particle) / Resolution: 2.62 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-ZLD:
N-{[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide / antibiotic*YM

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsRIBOSOME/ANTIBIOTIC / Mitochondrial ribosome / Oxazolidinone / antibiotics / RIBOSOME-ANTIBIOTIC complex

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