Deciphering linezolid-induced hematologic toxicity: Targeting TOP2A and TOP2B via its primary metabolite PNU142586

Area of Science:

• Pharmacology
• Molecular Biology
• Toxicology

Background:

• Linezolid is a crucial antibiotic for multidrug-resistant tuberculosis and Gram-positive infections.
• Prolonged linezolid use can cause severe hematologic toxicity, with unclear mechanisms involving its metabolites.
• Elevated exposure to linezolid's primary metabolite, PNU142586, correlates with toxicity risk, independent of kidney function.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying linezolid-induced hematologic toxicity.
• To identify the specific targets and pathways affected by the linezolid metabolite PNU142586.
• To provide a basis for developing safer antibiotics and improved clinical monitoring.

Main Methods:

• Clinical study correlating PNU142586 exposure with toxicity.
• Molecular, cellular, and in vivo studies to identify PNU142586 targets.
• Assays to assess PNU142586's effects on DNA topoisomerases and cellular processes.

Main Results:

• DNA topoisomerase 2-alpha (TOP2A) and 2-beta (TOP2B) were identified as primary targets of PNU142586.
• PNU142586 disrupts DNA replication and transcription by inhibiting TOP2A/TOP2B binding and ATP hydrolysis.
• Observed effects include antiproliferative and cytotoxic impacts, notably mitochondrial dysfunction.

Conclusions:

• PNU142586's interaction with TOP2A/TOP2B explains linezolid-induced hematologic toxicity.
• This provides mechanistic insight into antibiotic-associated adverse effects.
• Findings support identifying biomarkers for safer linezolid use and guiding future antibiotic development.