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Publications

Journal Article Ppublish

PubMed: 40435237 DOI: 10.1126/sciadv.adt5833

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

Sci Adv 11(22):eadt5833

Authors: Vo Thuy Anh Thu, Nguyen Quynh Nhu, Nguyen Thi Van Anh, So-An Lim, Hyeon-Jeong Seong, Jony Md Rasheduzzaman, Uijin Kim, Hyun-Soo Cho, Soedarsono Soedarsono, Jae-Gook Shin, Yong-Soon Cho

Affiliations

  • Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan, Korea. Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
  • Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan, Korea.
  • Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
  • Department of Systems Biology, Yonsei University, Seoul 03722, Republic of Korea.
  • Department of Systems Biology, Yonsei University, Seoul 03722, Republic of Korea. Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul 03722, Republic of Korea.
  • Sub-pulmonology Department of Internal Medicine, Faculty of Medicine, Hang Tuah University, Surabaya, Indonesia.
  • Dr. Soetomo Academic General Hospital, Surabaya, Indonesia.
  • Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan, Korea. Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea. Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Korea.

Abstract

Linezolid, an oxazolidinone antibiotic, is widely used to treat multidrug-resistant tuberculosis and drug-resistant Gram-positive infections. However, prolonged use is associated with severe hematologic toxicity, the underlying mechanisms of which remain incompletely understood, particularly regarding the role of linezolid metabolites. Our clinical study indicates that elevated exposure to PNU142586, a primary metabolite of linezolid, is associated with an increased risk of linezolid-induced toxicity, even in the absence of renal impairment. To elucidate its mechanism, we identify DNA topoisomerase 2-α (TOP2A) and DNA topoisomerase 2-β (TOP2B) as primary targets of PNU142586 at molecular, cellular, and in vivo levels. PNU142586 disrupts replication and transcription by impeding DNA binding to TOP2A and TOP2B with a favorable conformation for cleavage and by inhibiting adenosine 5'-triphosphate hydrolysis, ultimately leading to antiproliferative and cytotoxic effects, including mitochondrial dysfunction. The present study thus provides mechanistic insight into linezolid-induced hematologic toxicity and offers a foundation for safer antibiotic development and improved clinical monitoring through biomarker identification.

MeSH

Biological Science Disciplines, Pharmaceutical Preparations, Linezolid