1. Int J Antimicrob Agents. 2019 Nov;54(5):661-667. doi:
10.1016/j.ijantimicag.2019.07.021. Epub 2019 Jul 30.

Prolonged inhibition and incomplete recovery of mitochondrial function in
oxazolidinone-treated megakaryoblastic cell lines.

Milosevic TV(1), Vertenoeil G(2), Payen VL(3), Sonveaux P(3), Tulkens PM(1),
Constantinescu SN(2,4,5), Van Bambeke F(1).

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium.
(2)Signal Transduction and Molecular Haematology, Ludwig Institute for Cancer
Research, Brussels Branch, Brussels, Belgium; de Duve Institute, Université 
catholique de Louvain, Brussels, Belgium.
(3)Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical 
Research, Université catholique de Louvain, Brussels, Belgium.
(4) de Duve Institute, Université catholique de Louvain, Brussels, Belgium; 
(5) Walloon Excellence in Life Science and Biotechnology, Brussels, Belgium.

Electronic address:

Thrombocytopenia is commonly seen in patients receiving linezolid for >14 days.
Linezolid is a reversible inhibitor of mitochondrial function in various cell
types. This study investigated the inhibitory effects of linezolid and tedizolid,
and their potential recovery on (i) CYTox I expression (subunit I of cytochrome
c-oxidase; encoded by the mitochondrial genome), (ii) cytochrome c-oxidase
activity and (iii) mitochondrial respiration (Seahorse bioanalysis) in two
megakaryocytic cell lines [UT-7 WT (human acute megakaryoblastic leukaemia cells)
and UT-7 MPL (transduced to express the thrombopoietin receptor)]. Cells were
exposed to linezolid (0.5-25 mg/L) or tedizolid (0.1-5 mg/L) for up to 5 days and
recovery followed after drug removal. Both oxazolidinones caused concentration-
and time-dependent inhibition of CYTox I expression, cytochrome c-oxidase
activity and mitochondrial spare capacity. On electron microscopy, mitochondria
appeared dilated with a loss of cristae. Globally, tedizolid exerted stronger
effects than linezolid. While CYTox I expression recovered completely after 6
days of drug washout, only partial (linezolid) or no (tedizolid) recovery of
cytochrome c-oxidase activity, and no rescue of mitochondrial spare capacity
(after 3 days) was observed. Thus, and in contrast to previous studies using a
variety of cell lines unrelated to megakaryocytic lineages, the inhibitory
effects exerted by oxazolidinones on the mitochondrial function of
megakaryoblastic cells appear to be particularly protracted. Given the dynamics
of platelet production and destruction, these results may explain why
oxazolidinone-induced thrombocytopenia is one of the most common side effects in 
patients exposed to these antibiotics.

Copyright  2019 Elsevier B.V. and International Society of Chemotherapy. All
rights reserved.

DOI: 10.1016/j.ijantimicag.2019.07.021 
PMID: 31374333