Polymyxin B causes DNA damage in HK-2 cells and mice

B. Yun, T. Zhang, M. A. K. Azad, J. Wang, C. J. Nowell, P. Kalitsis, T. Velkov, D. F. Hudson, J. Li

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3 Citations (Scopus)

Abstract

Increasing incidence of multidrug-resistant bacteria presents an imminent risk to global health. Polymyxins are ‘last-resort’ antibiotics against Gram-negative ‘superbugs’; however, nephrotoxicity remains a key impediment in their clinical use. Molecular mechanisms underlying this nephrotoxicity remain poorly defined. Here, we examined the pathways which led to polymyxin B induced cell death in vitro and in vivo. Human proximal tubular cells were treated with polymyxin B (12.5–100 μM) for up to 24 h and showed a significant increase in micronuclei frequency, as well as abnormal mitotic events (over 40% in treated cells, p < 0.05). Time-course studies were performed using a mouse nephrotoxicity model (cumulative 72 mg/kg). Kidneys were collected over 48 h and investigated for histopathology and DNA damage. Notable increases in γH2AX foci (indicative of double-stranded breaks) were observed in both cell culture (up to ~ 44% cells with 5+ foci at 24 h, p < 0.05) and mice treated with polymyxin B (up to ~ 25%, p < 0.05). Consistent with these results, in vitro assays showed high binding affinity of polymyxin B to DNA. Together, our results indicate that polymyxin B nephrotoxicity is associated with DNA damage, leading to chromosome missegregation and genome instability. This novel mechanistic information may lead to new strategies to overcome the nephrotoxicity of this important last-line class of antibiotics.

Original languageEnglish
Pages (from-to)2259-2271
Number of pages13
JournalArchives of Toxicology
Volume92
Issue number7
DOIs
Publication statusPublished - Jul 2018

Keywords

  • Cell biology
  • Cellular toxicity
  • DNA damage
  • Nephrotoxicity
  • Polymyxins

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