Mechanisms of hepatotoxicity associated with the monocyclic β-lactam antibiotic BAL30072

BAL30072 is a new monocyclic β-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose c...

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Bibliographic Details
Published in:Archives of toxicology 2017-11, Vol.91 (11), p.3647-3662
Main Authors: Paech, Franziska, Messner, Simon, Spickermann, Jochen, Wind, Mathias, Schmitt-Hoffmann, Anne-Hortense, Witschi, Anne Therese, Howell, Brett A., Church, Rachel J., Woodhead, Jeff, Engelhardt, Marc, Krähenbühl, Stephan, Maurer, Martina
Format: Article
Language:English
Subjects:
Acetylcysteine
Adenosine Triphosphate - metabolism
Amides
Antibiotics
Apoptosis
Apoptosis - drug effects
Bacteria
Biomedical and Life Sciences
Biomedicine
Cell Survival - drug effects
Chemical and Drug Induced Liver Injury - metabolism
Chemical and Drug Induced Liver Injury - pathology
Drug resistance
Electron transport
Electron Transport - drug effects
Electron transport chain
Environmental Health
Fatty acids
Glycolysis
Glycolysis - drug effects
Gram-negative bacteria
Hep G2 Cells
Hepatocellular carcinoma
Hepatocytes
Hepatocytes - drug effects
Hepatotoxicity
Humans
Kupffer Cells - drug effects
Lipopolysaccharides - toxicity
Liver
Male
Membrane potential
Metabolism
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Mitochondria
Monobactams - adverse effects
Monobactams - blood
Monobactams - toxicity
Occupational Medicine/Industrial Medicine
Organ Toxicity and Mechanisms
Oxygen consumption
Pharmacology/Toxicology
Progenitor cells
Rats
Reactive oxygen species
Rodents
Solute Carrier Organic Anion Transporter Family Member 1b1 - metabolism
Solute Carrier Organic Anion Transporter Family Member 1B3 - metabolism
Thiazoles - adverse effects
Thiazoles - blood
Thiazoles - toxicity
Toxicity
Transaminase
β-Lactam antibiotics
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Summary:BAL30072 is a new monocyclic β-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations. Our investigations demonstrated a concentration- and time-dependent reduction of the ATP content of BAL30072-treated HepG2 cells and liver microtissues. BAL30072 impaired oxygen consumption by HepG2 cells at clinically relevant concentrations, inhibited complexes II and III of the mitochondrial electron transport chain, increased the production of reactive oxygen species (ROS), and reduced the mitochondrial membrane potential. Furthermore, BAL 30072 impaired mitochondrial fatty acid metabolism, inhibited glycolysis, and was associated with hepatocyte apoptosis. Co-administration of N -acetyl- l -cysteine partially protected hepatocytes from BAL30072-mediated toxicity, underscoring the role of oxidative damage in the observed hepatocellular toxicity. In conclusion, BAL30072 is toxic for liver mitochondria and inhibits glycolysis at clinically relevant concentrations. Impaired hepatic mitochondrial function and inhibition of glycolysis can explain liver injury observed in human subjects receiving long-term treatment with this compound.
ISSN:0340-5761
1432-0738
DOI:10.1007/s00204-017-1994-x