Azithromycin and mitochondrial biogenisis

Interesting:

The effects of a variety of oxazolidinones, with different antibacterial potencies, including linezolid, on mitochondrial protein synthesis were determined in intact mitochondria isolated from rat heart and liver and rabbit heart and bone marrow. The results demonstrate that a general feature of the oxazolidinone class of antibiotics is the inhibition of mammalian mitochondrial protein synthesis. Inhibition was similar in mitochondria from all tissues studied. Further, oxazolidinones that were very potent as antibiotics were uniformly potent in inhibiting mitochondrial protein synthesis. These results were compared to the inhibitory profiles of other antibiotics that function by inhibiting bacterial protein synthesis. Of these, chloramphenicol and tetracycline were significant inhibitors of mammalian mitochondrial protein synthesis while the macrolides, lincosamides, and aminoglycosides were not. Development of future antibiotics from the oxazolidinone class will have to evaluate potential mitochondrial toxicity.

Several classes of antibiotics function by binding to the bacterial ribosome and inhibiting bacterial protein synthesis. These include aminoglycosides, macrolides, tetracyclines, lincosamides, and chloramphenicol. Linezolid (Zyvox), an oxazolidinone recently approved for clinical use, represents an important new class of antibiotic that has been very effective in treating multidrug-resistant gram-positive pathogens (for reviews see references 5 and 20).

The mitochondrial protein synthesis machinery is in many ways similar to the prokaryotic machinery and as a result may be a target for antibiotics that function by binding to the bacterial ribosome (8). Significant evidence has shown that bone marrow suppression, often reported as a dose-dependent and reversible toxic side effect of chloramphenicol therapy in humans, is caused by inhibition of mitochondrial protein synthesis (for reviews, see references 33 and 39). The oxazolidinones have been shown to bind to the large bacterial ribosomal subunit at a site that overlaps the chloramphenicol binding site and to inhibit bacterial protein synthesis (12, 24). Thus, oxazolidinones have the potential to bind to mitochondrial ribosomes and to inhibit mitochondrial protein synthesis. Dose-dependent and reversible bone marrow suppression has been noted as a side effect of treatment with linezolid (17, 22), consistent with inhibition of mitochondrial protein synthesis, as has been noted for chloramphenicol (15, 39). Pharmacia (now Pfizer) has synthesized newer oxazolidinones with increased antibiotic potency, in particular ones that would be effective against gram-negative bacteria (6, 16). While linezolid was essentially nontoxic in a rat toxicity assay (100 mg/kg of body weight, twice daily for 30 days) (10), as noted herein, some of the newer compounds were significantly more toxic, leading to rat deaths within the 30-day assay period. We hypothesized that the animal toxicity exhibited by some of the more potent oxazolidinone antibiotics, as well as the mild side effects of linezolid, was caused by inhibiting mammalian mitochondrial protein synthesis. To test this hypothesis, a variety of oxazolidinones with widely varying degrees of antibiotic potency, including linezolid and eperezolid, were evaluated for their abilities to inhibit mitochondrial protein synthesis. These results were compared to those of other clinically approved antibiotics that function by inhibiting bacterial protein synthesis.