antibiotics & mitochondria

[Guest guest]

Cites 0, 2, 6, and perhaps 4 are free online via links in PubMed.

- - - -

0: Antimicrob Agents Chemother. 1990 Jan;34(1):167-9.

*Ciprofloxacin does not inhibit mitochondrial functions but other

antibiotics do.*

Riesbeck K, Bredberg A, Forsgren A.

Department of Medical Microbiology, University of Lund, Malmö General

Hospital, Sweden.

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

1: Mol Cell. 2007 May 11;26(3):393-402.

*The site of action of oxazolidinone antibiotics in living bacteria and

in human mitochondria.*

Leach KL et al.

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

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

2: Antimicrob Agents Chemother. 2007 Jan;51(1):54-63. Epub 2006 Nov 6.

*Influence on mitochondria and cytotoxicity of different antibiotics

administered in high concentrations on primary human osteoblasts and

cell lines.*

Duewelhenke N, Krut O, Eysel P.

Klinik und Poliklinik für Orthopädie, Universitätsklinikum Köln,

ph-Stelzmann-Str. 24, 50931 Köln, Germany.

.Duewelhenke@...

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

3: FEBS Lett. 2005 Nov 21;579(28):6423-7. Epub 2005 Nov 2.

*Antibiotic susceptibility of mammalian mitochondrial translation.*

Zhang L, Ging NC, Komoda T, Hanada T, Suzuki T, Watanabe K.

Department of Integrated Biosciences, Graduate School of Frontier

Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba

277-8562, Japan.

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

4: J Pharmacol Exp Ther. 1995 Jul;274(1):194-9.

*Effects of nephrotoxic beta-lactam antibiotics on the mitochondrial

metabolism of monocarboxylic substrates.*

Tune BM, Hsu CY.

Laboratory of Renal Pharmacology, Department of Pediatrics, Stanford,

California, USA.

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

5: Nat Genet. 1993 Jul;4(3):289-94.

*Mitochondrial ribosomal RNA mutation associated with both

antibiotic-induced and non-syndromic deafness.*

Prezant TR et al.

Ahmanson Department of Pediatrics Spielberg Pediatric Research

Center, Cedars-Sinai Medical Center, Los Angeles, California.

Maternally transmitted non-syndromic deafness was described recently

both in pedigrees with susceptibility to aminoglycoside ototoxicity and

in a large Arab-Israeli pedigree. Because of the known action of

aminoglycosides on bacterial ribosomes, we analysed the sequence of the

mitochondrial rRNA genes of three unrelated patients with familial

aminoglycoside-induced deafness. We also sequenced the complete

mitochondrial genome of the Arab-Israeli pedigree. All four families

shared a nucleotide 1555 A to G substitution in the 12S rRNA gene, a

site implicated in aminoglycoside activity. Our study offers the first

description of a mitochondrial rRNA mutation leading to disease, the

first cases of non-syndromic deafness caused by a mitochondrial DNA

mutation and the first molecular genetic study of antibiotic-induced

ototoxicity.

PMID: 7689389

6: J Am Soc Nephrol. 1990 Nov;1(5):815-21.

*

The renal mitochondrial toxicity of beta-lactam antibiotics: in vitro

effects of cephaloglycin and imipenem.*

Tune BM, Hsu CY.

Department of Pediatrics, Stanford University School of Medicine, CA 94305.

The nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin,

and imipenem produce irreversible injury to renal mitochondrial anionic

substrate uptake and respiration after 1 to 2 h of in vivo exposure.

Toxicity during in vitro exposure is nearly identical but is immediate

in onset and is reversed by the mitochondria being washed or the

substrate concentrations being increased. A model of injury that

accounts for these findings proposes that the beta-lactams fit carriers

for mitochondrial substrate uptake, causing inhibition that is initially

reversible and becomes irreversible as the antibiotics acylate the

transporters. These studies were designed to create an environment of

prolonged in vitro exposure, first, to determine whether toxicity

becomes irreversible with time and, second, to study the molecular

properties of toxicity. Respiration with and the uptake of succinate and

ADP were measured in rabbit renal cortical mitochondria exposed for 2 to

6 h to 300 to 3,000 micrograms of cephalexin (nontoxic) or cephaloglycin

or imipenem (nephrotoxic) per mL and then washed to remove the

antibiotic. In vitro cephalexin reduced respiration only slightly and

was therefore not studied further. Cephaloglycin and imipenem

irreversibly reduced both respiration and succinate uptake. ADP uptake

was unaffected by cephaloglycin and was slightly reduced by imipenem.

Finally, cilastatin, which prevents the tubular necrosis produced by

imipenem in vivo, reduced its mitochondrial toxicity in vitro. It is

concluded that the pattern of in vitro injury of the nephrotoxic

beta-lactams to mitochondrial substrate uptake and respiration evolves

in a time-dependent and concentration-dependent manner, consistent with

the proposed model of acylation and inactivation of substrate

transporters, and that the protective action of cilastatin against

imipenem occurs at least partly at a subcellular level.

PMID: 2133431

eof