Advances in Autism Research
compiled by Teresa Binstock
for Autism Research Institute
April 2008

Mitochondria and Antibiotics

Many parents of children who regressed into autism following a vaccination incident also report that the child had been sick, recently sick, or had received a large number of antibiotics, often for recurrent otitis media. The citations herein report that some antibiotics affect mitochondria function, thus prompting concern regarding the interplay among antibiotics, vaccinations, and transient or chronic mitochondria dysfunction.

1. Ciprofloxacin does not inhibit mitochondrial functions but other antibiotics do

Riesbeck K et al.
Antimicrob Agents Chemother. 1990 Jan;34(1):167-9. free online
http://aac.asm.org/cgi/reprint/34/1/167?view=long&pmid=2327755

At clinical concentrations, ciprofloxacin did not inhibit mitochondrial DNA replication, oxidative phosphorylation, protein synthesis, or mitochondrial mass (transmembrane potential). No difference in supercoiled forms of DNA was observed. The tetracyclines and chloramphenicol inhibited protein synthesis at clinically achievable concentrations, while rifampin, fusidic acid, and clindamycin did not.
PMID: 2327755

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

Leach KL et al.
Mol Cell. 2007 May 11;26(3):393-402.

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.
PMID: 17499045

3. Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines

Duewelhenke N et al.
Antimicrob Agents Chemother. 2007 Jan;51(1):54-63.
http://aac.asm.org/cgi/reprint/51/1/54

Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 microg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 microg/ml for macrolides, clindamycin, and rifampin, 60 to 80 microg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 microg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.
PMID: 17088489

4. Antibiotic susceptibility of mammalian mitochondrial translation

Zhang L et al.
FEBS Lett. 2005 Nov 21;579(28):6423-7.

All medically useful antibiotics should have the potential to distinguish between target microbes (bacteria) and host cells. Although many antibiotics that target bacterial protein synthesis show little effect on the translation machinery of the eukaryotic cytoplasm, it is unclear whether these antibiotics target or not the mitochondrial translation machinery. We employed an in vitro translation system from bovine mitochondria, which consists of mitochondrial ribosomes and mitochondrial elongation factors, to estimate the effect of antibiotics on mitichondrial protein synthesis. Tetracycline and thiostrepton showed similar inhibitory effects on both Escherichia coli and mitochondrial protein synthesis. The mitochondrial system was more resistant to tiamulin, macrolides, virginiamycin, fusidic acid and kirromycin than the E. coli system. The present results, taken together with atomic structure of the ribosome, may provide useful information for the rational design of new antibiotics having less adverse effects in humans and animals.
PMID: 16271719

5. Effects of nephrotoxic beta-lactam antibiotics on the mitochondrial metabolism of monocarboxylic substrates

Tune BM, Hsu CY.
J Pharmacol Exp Ther. 1995 Jul;274(1):194-9.

The nephrotoxic beta-lactam antibiotics (beta-lactams) cephaloridine, cephaloglycin and imipenem are toxic to the mitochondrial transport and (secondarily) oxidation of succinate and other dicarboxylic substrates. However, compared to cephaloglycin, cephaloridine is minimally toxic to the mitochondrial uptake and uncoupled oxidation of the short-chain fatty anion butyrate. Further studies were therefore done to compare the early effects of nephrotoxic doses (300 mg/kg body weight) of imipenem, cephaloridine and cephaloglycin on the mitochondrial metabolism of three important monocarboxylic substrates, butyrate, valerate and pyruvate, in rabbit renal cortex. The following was found: 1) imipenen reduces the oxidation of all three monocarboxylates, within 0.5 to 1 hr after administration. 2) The respiratory toxicity of cephaloglycin is essentially the same as that of imipenem with all three substrates. 3) cephaloridine causes little or no toxicity to pyruvate or butyrate oxidation and is significantly less toxic than imipenem or cephaloglycin to valerate oxidation. 4) The effects of the three beta-lactams on butyrate and pyruvate uptake parallel their effects on butyrate and pyruvate oxidation. CONCLUSIONS: Imipenem and cephaloglycin have essentially the same patterns of toxicity to the mitochondrial metabolism of all metabolic substrates that have been tested. Although cephaloridine has similar effects on dicarboxylic substrates, it is significantly less toxic to the mitochondrial metabolism of pyruvate and the short-chain fatty anions. It is proposed that cephaloridine's zwitterionic charge may restrict its ability to acylate monocarboxylic and other anionic carriers, resulting in less nephrotoxicity than might otherwise result from its uniquely high intracellular concentrations and singular ability among the toxic beta-lactams to produce oxidative injury.
PMID: 7616399