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Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP-1 Monocytes.

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Milosevic, Tamara [UCL] Payen, Valéry [UCL] Sonveaux, Pierre [UCL] Muccioli, Giulio [UCL] Tulkens, Paul M. [UCL] Van Bambeke, Françoise [UCL]

Linezolid, the first clinically available oxazolidinone antibiotic, causes potentially severe toxicities (myelosuppression, lactic acidosis, and neuropathies) ascribed to impairment of mitochondrial protein synthesis and consecutive mitochondrial dysfunction. Tedizolid, a newly approved oxazolidinone, shows an enhanced activity compared to linezolid but is also a more potent inhibitor of mitochondrial protein synthesis. We compared linezolid and tedizolid for (i) inhibition of the expression of subunit I of cytochrome -oxidase (CYTox I; Western blot analysis), (ii) cytochrome -oxidase activity (biochemical assay), (iii) mitochondrial oxidative metabolism (Seahorse technology), and (iv) alteration of mitochondrial ultrastructure (electron microscopy) using HL-60 promyelocytes and THP-1 monocytes exposed to microbiologically (multiples of modal MIC against ) and therapeutically ( - ) pertinent concentrations. Both drugs caused a rapid and complete (48 to 72 h) inhibition of CYTox I expression, cytochrome -oxidase activity, and spare respiratory capacity, with conspicuous swelling of the mitochondrial matrix and loss of their cristae. Globally, tedizolid was a more potent inhibitor than linezolid. For both drugs, all effects were quickly (48 to 72 h) and fully reversible upon drug withdrawal. Using an alternation of exposure to and withdrawal from drug mimicking their approved schedule of administration (twice daily and once daily [qD] for linezolid and tedizolid, respectively), only partial inhibition of CYTox I expression was noted for up to 96 h. Thus, rapid reversal of toxic effects upon discontinuous administration may mitigate oxazolidinone toxicity. Since tedizolid is given qD, this may help to explain its reported lower preclinical and clinical toxicity.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2018
Language Anglais
Journal information "Antimicrobial Agents and Chemotherapy" - Vol. 62, no. 3, p. e01599-17 [1-17] (2018)
Peer reviewed yes
Publisher American Society for Microbiology ((United States) Washington, DC)
issn 0066-4804
e-issn 1098-6596
Publication status Publié
Affiliations UCL - SSS/IREC - Institut de recherche expérimentale et clinique
UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
UCL - SSS/IREC/PEDI - Pôle de Pédiatrie
UCL - SSS/LDRI - Louvain Drug Research Institute
Keywords electron transport chain ; linezolid ; mitochondria ; mitochondrial metabolism ; mitochondrial proteins ; mitochondrial respiration ; oxazolidinones ; tedizolid
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Bibliographic reference Milosevic, Tamara ; Payen, Valéry ; Sonveaux, Pierre ; Muccioli, Giulio ; Tulkens, Paul M. ; et. al. Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP-1 Monocytes.. In: Antimicrobial Agents and Chemotherapy, Vol. 62, no. 3, p. e01599-17 [1-17] (2018)
Permanent URL http://hdl.handle.net/2078.1/199907