Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium.
Signal Transduction and Molecular Hematology Unit (SIGN), de Duve Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium.
Antimicrob Agents Chemother. 2024 Oct 8;68(10):e0053324. doi: 10.1128/aac.00533-24. Epub 2024 Sep 19.
Oxazolidinones (linezolid and tedizolid) adverse reactions include thrombocytopenia, the mechanism of which is still largely unknown. In cultured cells, oxazolidinones impair mitochondrial protein synthesis and oxidative metabolism. As mitochondrial activity is essential for megakaryocyte differentiation and maturation into platelets, we examined whether oxazolidinones impair these processes and alter, in parallel, the activity of mitochondrial cytochrome -oxidase (CYTOX; enzyme partly encoded by the mitochondrial genome) and cell morphology. Human CD34+ cells were isolated, incubated with cytokines (up to 14 days) and clinically relevant oxazolidinone concentrations or in control conditions, and used for (i) clonogenic assays [counting of megakaryocyte (CFU-Mk), granulocyte-monocyte (CFU-GM), burst-forming unit-erythroid (BFU-E) colonies]; (ii) the measure of the expression of megakaryocyte surface antigens (CD34 to CD41 and CD42); (iii) counting of proplatelets; (iv) the measurement of CYTOX activity; and (v) cell morphology (optic and electron microscopy). Oxazolidinones caused a significant decrease in BFU-E but not CFU-Mk or CFU-GM colonies. Yet, the megakaryocytic lineage was markedly affected, with a decreased differentiation of CD34+ into CD41+/CD42+ cells, an abolition of proplatelet formation and striking decrease in the numbers of large polylobulated nucleus megakaryocytes, with a complete loss of intracellular demarcation membrane system, disappearance of mitochondria, and suppression of CYTOX activity. These alterations were more marked in cells incubated with tedizolid than linezolid. These data suggest that oxazolidinones may induce thrombocytopenia by impairing megakaryocytic differentiation through mitochondrial dysfunction. Pharmacological interventions to prevent this toxicity might therefore be difficult as mitochondrial toxicity is most probably inherently linked to their antibacterial activity.
恶唑烷酮类（利奈唑胺和替加环素）的不良反应包括血小板减少症，其机制在很大程度上仍不清楚。在培养细胞中，恶唑烷酮类药物会损害线粒体蛋白合成和氧化代谢。由于线粒体活性对于巨核细胞分化和成熟为血小板至关重要，我们研究了恶唑烷酮类药物是否会损害这些过程，并平行改变线粒体细胞色素氧化酶（CYTOX；部分由线粒体基因组编码的酶）的活性和细胞形态。分离出人 CD34+细胞，用细胞因子（长达 14 天）和临床相关的恶唑烷酮浓度或对照条件孵育，并用于（i）集落形成测定[巨核细胞（CFU-Mk）、粒细胞-单核细胞（CFU-GM）、成红细胞集落形成单位（BFU-E）的计数]；（ii）巨核细胞表面抗原（CD34 到 CD41 和 CD42）表达的测量；（iii）血小板前体的计数；（iv）CYTOX 活性的测量；以及（v）细胞形态（光学和电子显微镜）。恶唑烷酮类药物显著降低 BFU-E，但不降低 CFU-Mk 或 CFU-GM 集落。然而，巨核细胞谱系受到明显影响，CD34+向 CD41+/CD42+细胞的分化减少，血小板前体形成被消除，多核巨核细胞数量明显减少，细胞内界膜系统完全丧失，线粒体消失，CYTOX 活性受到抑制。与利奈唑胺相比，替加环素孵育的细胞中这些变化更为明显。这些数据表明，恶唑烷酮类药物可能通过线粒体功能障碍损害巨核细胞分化来诱导血小板减少症。因此，预防这种毒性的药物干预可能很困难，因为线粒体毒性很可能与其抗菌活性内在相关。
