The interference of the macrolide antibiotics with mitochondrial protein synthesis

Abstract

1. Protein synthesis by isolated BHK-21 mitochondria was shown to be inhibited by the macrolides erythromycin, tylosin tartrate, spiramycin and carbomycin. Intact mitochondria from rat liver were insensitive to erythromycin, but inhibited by tylosin tartrate, spiramycin and carbomycin. 2. Cytochrome c oxidase formation in BHK-21 cells was unaffected by tylosin tartrate and spiramycin, but strongly inhibited by carbomycin. Mitochondrial protein synthesis in whole BHK-21 cells showed the same insensitivity to tylosin tartrate and spiramycin. 3. Peptidyl transferase activity of isolated rat-liver mitochondrial ribosomes was inhibited by tylosin tartrate, spiramycin and carbomycin, whereas chloramphenicol inhibition was reversed by erythromycin. Rather high antibiotic concentrations (200 μg/ml or higher) were necessary to obtain these effects. For Neurospora crassa mitochondrial ribosomes a similar response to these macrolides was found. Therefore mitochondrial ribosomes from N. crassa are markedly less sensitive to macrolides than yeast mitochondrial ribosomes. 4. It is shown that mammalian mitochondrial protein synthesis is sensitive to erythromycin, tylosin tartrate, spiramycin and carbomycin, but that for the first three antibiotics membrane barriers exist: for erythromycin the mitochondrial membrane is the barrier and for tylosin tartrate and spiramycin the cell membrane. 5. Amino acid incorporation by isolated mitochondria appears much more sensitive to inhibition by tylosin tartrate, spiramycin and carbomycin than the isolated 55-S ribosomes. For carbomycin this can be explained in part by the finding that carbomycin was concentrated by intact rat-liver mitochondria in vitro.